[{"result":{"data":{"method":"DeepDiveWithReviewer","timestamp":"2026-03-10 14:20:11.026841","user_id":"TWuFn4411RQmRel9PvGECQmyve8ZNzNd","user_name":"Daniel Clarke","published":true,"input":{"input":"ACE2"},"output":{"input":{"id":"512d63bf-fc43-4540-9ba4-4b183e19514d","key":"input","value":"ACE2","timestamp":"2026-03-10T14:20:11.722385","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"},"output":{"id":"09659558-1efd-4781-af07-b1447c257974","key":"output","value":"# ACE2 — concise summary for biologists\n\nACE2 is the functional entry receptor for SARS‑CoV and SARS‑CoV‑2: the viral spike (S) receptor‑binding domain (RBD) engages the ACE2 peptidase domain, supported by structural and functional studies that show a conserved binding mode and, for SARS‑CoV‑2, generally higher RBD affinity for human ACE2[^1][^2][^3][^4]. Full‑length ACE2 structures (complexed with the B0AT1 transporter) define ACE2 dimerization and the molecular interface for RBD recognition[^5].\n\nSpike activation by host proteases is required for ACE2‑dependent entry: TMPRSS2 primes S at the cell surface, and furin pre‑cleavage of SARS‑CoV‑2 S can reduce dependence on target‑cell proteases; pharmacologic inhibition of these proteases blocks entry in vitro and is a candidate antiviral strategy[^1][^6].\n\nACE2 expression is cell‑type specific and consistent with respiratory, intestinal and vascular tropism: ACE2 is expressed in lung alveolar epithelium, small intestinal enterocytes and vascular endothelium, which may contribute to multisystem manifestations of COVID‑19 and to routes of infection[^7][^9]. Viral engagement and downregulation of ACE2 can perturb the renin–angiotensin system and worsen lung injury, linking receptor usage to pathogenesis[^8].\n\nImplications: structural and biochemical mapping of the ACE2–S interface informs therapeutic design (neutralizing antibodies, soluble ACE2 decoys) and helps explain species/host‑range differences; targeting protease activation (e.g., TMPRSS2/furin) is an orthogonal intervention approach[^4][^1][^10].\n\n[^1]: Hoffmann, M., Kleine‑Weber, H., Schroeder, S., et al. SARS‑CoV‑2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell (2020).  \n[^2]: Zhou, P., Yang, X.‑L., Wang, X.‑G., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature (2020).  \n[^3]: Wrapp, D., Wang, N., Corbett, K. S., et al. Cryo‑EM structure of the 2019‑nCoV spike in the prefusion conformation. Science (2020).  \n[^4]: Lan, J., Ge, J., Yu, J., et al. Structure of the SARS‑CoV‑2 spike receptor‑binding domain bound to the ACE2 receptor. Nature (2020).  \n[^5]: Yan, R., Zhang, Y., Li, Y., et al. Structural basis for the recognition of SARS‑CoV‑2 by full‑length human ACE2. Science (2020).  \n[^6]: Shang, J., Wan, Y., Luo, C., et al. Cell entry mechanisms of SARS‑CoV‑2. Proc Natl Acad Sci U S A (2020).  \n[^7]: Hamming, I., Timens, W., Bulthuis, M. L. C., et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol (2004).  \n[^8]: Kuba, K., Imai, Y., Rao, S., et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus‑induced lung injury. Nat Med (2005).  \n[^9]: Gupta, A., Madhavan, M. V., Sehgal, K., et al. Extrapulmonary manifestations of COVID‑19. Nat Med (2020).  \n[^10]: Wan, Y., Shang, J., Graham, R., et al. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade‑Long Structural Studies of SARS Coronavirus. J Virol (2020).","timestamp":"2026-03-10T14:22:06.180216","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"},"prompt":{"id":"e1ce1771-4abf-4b6c-bff0-6ebc67ef75c6","key":"prompt","value":[{"role":"user","content":"# Our Summary\n# ACE2 — concise summary for biologists\n\nACE2 is the functional entry receptor for both SARS-CoV and SARS‑CoV‑2: the viral spike (S) receptor‑binding domain (RBD) engages the ACE2 peptidase domain, a finding supported by multiple structural and functional studies showing conserved binding modes and, for SARS‑CoV‑2, generally higher RBD affinity for human ACE2[^1][^2][^3][^4]. Full‑length ACE2 structures (in complex with the B0AT1 transporter) define ACE2 dimerization and the molecular interface for RBD recognition[^5].\n\nSpike activation by host proteases is essential for ACE2‑dependent entry: TMPRSS2 primes S at the cell surface and furin pre‑cleavage of SARS‑CoV‑2 S reduces dependence on target‑cell proteases; pharmacologic inhibition of these proteases blocks entry in vitro and is a candidate antiviral strategy[^1][^6].\n\nACE2 expression is cell‑type specific and broad enough to explain respiratory, intestinal and vascular tropism: ACE2 is abundant on lung alveolar epithelium, small intestinal enterocytes and vascular endothelium, which likely contributes to multisystem manifestations of COVID‑19 and to routes of infection[^7][^9]. Viral engagement and downregulation of ACE2 can perturb the renin–angiotensin system and worsen lung injury, linking receptor usage to pathogenesis[^8].\n\nImplications: structural and biochemical mapping of the ACE2–S interface guides therapeutic design (neutralizing antibodies, soluble ACE2 decoys) and explains species/host‑range differences; targeting protease activation (e.g., TMPRSS2/furin) is an orthogonal intervention approach[^4][^1][^10].\n\n[^1]: Hoffmann, M., Kleine‑Weber, H., Schroeder, S., et al. SARS‑CoV‑2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell (2020).  \n[^2]: Zhou, P., Yang, X.‑L., Wang, X.‑G., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature (2020).  \n[^3]: Wrapp, D., Wang, N., Corbett, K. S., et al. Cryo‑EM structure of the 2019‑nCoV spike in the prefusion conformation. Science (2020).  \n[^4]: Lan, J., Ge, J., Yu, J., et al. Structure of the SARS‑CoV‑2 spike receptor‑binding domain bound to the ACE2 receptor. Nature (2020).  \n[^5]: Yan, R., Zhang, Y., Li, Y., et al. Structural basis for the recognition of SARS‑CoV‑2 by full‑length human ACE2. Science (2020).  \n[^6]: Shang, J., Wan, Y., Luo, C., et al. Cell entry mechanisms of SARS‑CoV‑2. Proc Natl Acad Sci U S A (2020).  \n[^7]: Hamming, I., Timens, W., Bulthuis, M. L. C., et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol (2004).  \n[^8]: Kuba, K., Imai, Y., Rao, S., et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus‑induced lung injury. Nat Med (2005).  \n[^9]: Gupta, A., Madhavan, M. V., Sehgal, K., et al. Extrapulmonary manifestations of COVID‑19. Nat Med (2020).  \n[^10]: Wan, Y., Shang, J., Graham, R., et al. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade‑Long Structural Studies of SARS Coronavirus. J Virol (2020)."},{"role":"user","content":"# Feedback\nQuick critique (concise)\n- Overall: clear, well‑focused and cites appropriate primary studies.  \n- Wording to tighten (to stay strictly within cited evidence): avoid strong causal verbs like \"explain\" — prefer \"consistent with\" or \"helps explain\" when linking ACE2 distribution to clinical tropism. Replace \"abundant\" with \"expressed\" or \"highly expressed\" only where supported.  \n- Citation formatting: switch to markdown footnotes ([^1]) and use a single, consistent ordering. Do not place footnotes in the title.  \n- Minor factual check: the claim that SARS‑CoV‑2 RBD has \"generally higher RBD affinity for human ACE2\" is supported by structural/binding studies cited (Wrapp, Lan) — keep but retain the cited basis.  \n- Suggestion: use the revised, slightly more conservative wording below.\n\nRevised concise summary (footnotes in markdown; no footnotes in title)\nACE2 is the functional entry receptor for SARS‑CoV and SARS‑CoV‑2: the viral spike (S) receptor‑binding domain (RBD) engages the ACE2 peptidase domain, supported by structural and functional studies that show a conserved binding mode and, for SARS‑CoV‑2, generally higher RBD affinity for human ACE2[^1][^2][^3][^4]. Full‑length ACE2 structures (complexed with the B0AT1 transporter) define ACE2 dimerization and the molecular interface for RBD recognition[^5].\n\nSpike activation by host proteases is required for ACE2‑dependent entry: TMPRSS2 primes S at the cell surface, and furin pre‑cleavage of SARS‑CoV‑2 S can reduce dependence on target‑cell proteases; pharmacologic inhibition of these proteases blocks entry in vitro and is a candidate antiviral strategy[^1][^6].\n\nACE2 expression is cell‑type specific and consistent with respiratory, intestinal and vascular tropism: ACE2 is expressed in lung alveolar epithelium, small intestinal enterocytes and vascular endothelium, which may contribute to multisystem manifestations of COVID‑19 and to routes of infection[^7][^9]. Viral engagement and downregulation of ACE2 can perturb the renin–angiotensin system and worsen lung injury, linking receptor usage to pathogenesis[^8].\n\nImplications: structural and biochemical mapping of the ACE2–S interface informs therapeutic design (neutralizing antibodies, soluble ACE2 decoys) and helps explain species/host‑range differences; targeting protease activation (e.g., TMPRSS2/furin) is an orthogonal intervention approach[^4][^1][^10].\n\n[^1]: Hoffmann, M., Kleine‑Weber, H., Schroeder, S., et al. SARS‑CoV‑2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell (2020).  \n[^2]: Zhou, P., Yang, X.‑L., Wang, X.‑G., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature (2020).  \n[^3]: Wrapp, D., Wang, N., Corbett, K. S., et al. Cryo‑EM structure of the 2019‑nCoV spike in the prefusion conformation. Science (2020).  \n[^4]: Lan, J., Ge, J., Yu, J., et al. Structure of the SARS‑CoV‑2 spike receptor‑binding domain bound to the ACE2 receptor. Nature (2020).  \n[^5]: Yan, R., Zhang, Y., Li, Y., et al. Structural basis for the recognition of SARS‑CoV‑2 by full‑length human ACE2. Science (2020).  \n[^6]: Shang, J., Wan, Y., Luo, C., et al. Cell entry mechanisms of SARS‑CoV‑2. Proc Natl Acad Sci U S A (2020).  \n[^7]: Hamming, I., Timens, W., Bulthuis, M. L. C., et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol (2004).  \n[^8]: Kuba, K., Imai, Y., Rao, S., et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus‑induced lung injury. Nat Med (2005).  \n[^9]: Gupta, A., Madhavan, M. V., Sehgal, K., et al. Extrapulmonary manifestations of COVID‑19. Nat Med (2020).  \n[^10]: Wan, Y., Shang, J., Graham, R., et al. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade‑Long Structural Studies of SARS Coronavirus. J Virol (2020)."},{"role":"user","content":"In light of the feedback, improve our summary.\nOutput in markdown, start with a title, use footnote formatting (e.g. [^1]) for citations.\nEnsure citation formatting of the summary uses markdown footnotes and consistent with the source material.\nNo footnotes in titles. Do not include a heading for references, just include footnotes."}],"timestamp":"2026-03-10T14:21:31.24385","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"},"review":{"id":"d855ea8a-9562-43c8-a580-f67a68a71eb4","key":"review","value":"Quick critique (concise)\n- Overall: clear, well‑focused and cites appropriate primary studies.  \n- Wording to tighten (to stay strictly within cited evidence): avoid strong causal verbs like \"explain\" — prefer \"consistent with\" or \"helps explain\" when linking ACE2 distribution to clinical tropism. Replace \"abundant\" with \"expressed\" or \"highly expressed\" only where supported.  \n- Citation formatting: switch to markdown footnotes ([^1]) and use a single, consistent ordering. Do not place footnotes in the title.  \n- Minor factual check: the claim that SARS‑CoV‑2 RBD has \"generally higher RBD affinity for human ACE2\" is supported by structural/binding studies cited (Wrapp, Lan) — keep but retain the cited basis.  \n- Suggestion: use the revised, slightly more conservative wording below.\n\nRevised concise summary (footnotes in markdown; no footnotes in title)\nACE2 is the functional entry receptor for SARS‑CoV and SARS‑CoV‑2: the viral spike (S) receptor‑binding domain (RBD) engages the ACE2 peptidase domain, supported by structural and functional studies that show a conserved binding mode and, for SARS‑CoV‑2, generally higher RBD affinity for human ACE2[^1][^2][^3][^4]. Full‑length ACE2 structures (complexed with the B0AT1 transporter) define ACE2 dimerization and the molecular interface for RBD recognition[^5].\n\nSpike activation by host proteases is required for ACE2‑dependent entry: TMPRSS2 primes S at the cell surface, and furin pre‑cleavage of SARS‑CoV‑2 S can reduce dependence on target‑cell proteases; pharmacologic inhibition of these proteases blocks entry in vitro and is a candidate antiviral strategy[^1][^6].\n\nACE2 expression is cell‑type specific and consistent with respiratory, intestinal and vascular tropism: ACE2 is expressed in lung alveolar epithelium, small intestinal enterocytes and vascular endothelium, which may contribute to multisystem manifestations of COVID‑19 and to routes of infection[^7][^9]. Viral engagement and downregulation of ACE2 can perturb the renin–angiotensin system and worsen lung injury, linking receptor usage to pathogenesis[^8].\n\nImplications: structural and biochemical mapping of the ACE2–S interface informs therapeutic design (neutralizing antibodies, soluble ACE2 decoys) and helps explain species/host‑range differences; targeting protease activation (e.g., TMPRSS2/furin) is an orthogonal intervention approach[^4][^1][^10].\n\n[^1]: Hoffmann, M., Kleine‑Weber, H., Schroeder, S., et al. SARS‑CoV‑2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell (2020).  \n[^2]: Zhou, P., Yang, X.‑L., Wang, X.‑G., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature (2020).  \n[^3]: Wrapp, D., Wang, N., Corbett, K. S., et al. Cryo‑EM structure of the 2019‑nCoV spike in the prefusion conformation. Science (2020).  \n[^4]: Lan, J., Ge, J., Yu, J., et al. Structure of the SARS‑CoV‑2 spike receptor‑binding domain bound to the ACE2 receptor. Nature (2020).  \n[^5]: Yan, R., Zhang, Y., Li, Y., et al. Structural basis for the recognition of SARS‑CoV‑2 by full‑length human ACE2. Science (2020).  \n[^6]: Shang, J., Wan, Y., Luo, C., et al. Cell entry mechanisms of SARS‑CoV‑2. Proc Natl Acad Sci U S A (2020).  \n[^7]: Hamming, I., Timens, W., Bulthuis, M. L. C., et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol (2004).  \n[^8]: Kuba, K., Imai, Y., Rao, S., et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus‑induced lung injury. Nat Med (2005).  \n[^9]: Gupta, A., Madhavan, M. V., Sehgal, K., et al. Extrapulmonary manifestations of COVID‑19. Nat Med (2020).  \n[^10]: Wan, Y., Shang, J., Graham, R., et al. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade‑Long Structural Studies of SARS Coronavirus. J Virol (2020).","timestamp":"2026-03-10T14:20:49.983028","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"},"deepdive_v1":{"id":"91108308-4a55-4c08-b661-c4b7ec7fbf94","key":"deepdive_v1","value":{"input":"ACE2"},"timestamp":"2026-03-10T14:20:11.724442","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"},"deepdive_v1.input":{"id":"7194d4fa-3113-4a4d-bbbf-c9935a8e3ae8","key":"deepdive_v1.input","value":"ACE2","timestamp":"2026-03-10T14:20:11.725974","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"},"deepdive_v1.output":{"id":"2d37778a-0217-4d4d-996f-96fe1f4686a0","key":"deepdive_v1.output","value":"# ACE2 — concise summary for biologists\n\nACE2 is the functional entry receptor for both SARS-CoV and SARS‑CoV‑2: the viral spike (S) receptor‑binding domain (RBD) engages the ACE2 peptidase domain, a finding supported by multiple structural and functional studies showing conserved binding modes and, for SARS‑CoV‑2, generally higher RBD affinity for human ACE2[^1][^2][^3][^4]. Full‑length ACE2 structures (in complex with the B0AT1 transporter) define ACE2 dimerization and the molecular interface for RBD recognition[^5].\n\nSpike activation by host proteases is essential for ACE2‑dependent entry: TMPRSS2 primes S at the cell surface and furin pre‑cleavage of SARS‑CoV‑2 S reduces dependence on target‑cell proteases; pharmacologic inhibition of these proteases blocks entry in vitro and is a candidate antiviral strategy[^1][^6].\n\nACE2 expression is cell‑type specific and broad enough to explain respiratory, intestinal and vascular tropism: ACE2 is abundant on lung alveolar epithelium, small intestinal enterocytes and vascular endothelium, which likely contributes to multisystem manifestations of COVID‑19 and to routes of infection[^7][^9]. Viral engagement and downregulation of ACE2 can perturb the renin–angiotensin system and worsen lung injury, linking receptor usage to pathogenesis[^8].\n\nImplications: structural and biochemical mapping of the ACE2–S interface guides therapeutic design (neutralizing antibodies, soluble ACE2 decoys) and explains species/host‑range differences; targeting protease activation (e.g., TMPRSS2/furin) is an orthogonal intervention approach[^4][^1][^10].\n\n[^1]: Hoffmann, M., Kleine‑Weber, H., Schroeder, S., et al. SARS‑CoV‑2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell (2020).  \n[^2]: Zhou, P., Yang, X.‑L., Wang, X.‑G., et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature (2020).  \n[^3]: Wrapp, D., Wang, N., Corbett, K. S., et al. Cryo‑EM structure of the 2019‑nCoV spike in the prefusion conformation. Science (2020).  \n[^4]: Lan, J., Ge, J., Yu, J., et al. Structure of the SARS‑CoV‑2 spike receptor‑binding domain bound to the ACE2 receptor. Nature (2020).  \n[^5]: Yan, R., Zhang, Y., Li, Y., et al. Structural basis for the recognition of SARS‑CoV‑2 by full‑length human ACE2. Science (2020).  \n[^6]: Shang, J., Wan, Y., Luo, C., et al. Cell entry mechanisms of SARS‑CoV‑2. Proc Natl Acad Sci U S A (2020).  \n[^7]: Hamming, I., Timens, W., Bulthuis, M. L. C., et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol (2004).  \n[^8]: Kuba, K., Imai, Y., Rao, S., et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus‑induced lung injury. Nat Med (2005).  \n[^9]: Gupta, A., Madhavan, M. V., Sehgal, K., et al. Extrapulmonary manifestations of COVID‑19. Nat Med (2020).  \n[^10]: Wan, Y., Shang, J., Graham, R., et al. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade‑Long Structural Studies of SARS Coronavirus. J Virol (2020).","timestamp":"2026-03-10T14:20:49.98013","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"},"deepdive_v1.prompt":{"id":"bb86beeb-c604-4be4-9504-143c25eedef7","key":"deepdive_v1.prompt","value":[{"role":"user","content":"Search: ACE2"},{"role":"user","content":"Results: ## Source Material\nHere are the abstracts of the top highly cited studies relevant to the search.\n\n### SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.\n\nThe recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.\n\nCited by: 14229  \nCite this article: Hoffmann, Markus., Kleine-Weber, Hannah., Schroeder, Simon., et al. **SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.** *Cell (2020)*. doi:10.1016/j.cell.2020.02.052\n\n### A pneumonia outbreak associated with a new coronavirus of probable bat origin.\n\nSince the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1-4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5-7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.\n\nCited by: 13808  \nCite this article: Zhou, Peng., Yang, Xing-Lou., Wang, Xian-Guang., et al. **A pneumonia outbreak associated with a new coronavirus of probable bat origin.** *Nature (2020)*. doi:10.1038/s41586-020-2012-7\n\n### Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.\n\nThe outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.\n\nCited by: 6424  \nCite this article: Wrapp, Daniel., Wang, Nianshuang., Corbett, Kizzmekia S., et al. **Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.** *Science (2020)*. doi:10.1126/science.abb2507\n\n### Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.\n\nThe emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S 1 /S 2  subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.\n\nCited by: 6273  \nCite this article: Walls, Alexandra C., Park, Young-Jun., Tortorici, M Alejandra., et al. **Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.** *Cell (2020)*. doi:10.1016/j.cell.2020.02.058\n\n### Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.\n\nA new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world 1-3 . Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor 4 . Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses 1-3,5 . The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.\n\nCited by: 4501  \nCite this article: Lan, Jun., Ge, Jiwan., Yu, Jinfang., et al. **Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.** *Nature (2020)*. doi:10.1038/s41586-020-2180-5\n\n### Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.\n\nSpike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells. Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV.\n\nCited by: 4368  \nCite this article: Li, Wenhui., Moore, Michael J., Vasilieva, Natalya., et al. **Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.** *Nature (2003)*. doi:10.1038/nature02145\n\n### Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.\n\nSevere acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS-CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations.\n\nCited by: 4023  \nCite this article: Hamming, I., Timens, W., Bulthuis, M L C., et al. **Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.** *J Pathol (2004)*. doi:10.1002/path.1570\n\n### Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.\n\nAngiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B 0 AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B 0 AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.\n\nCited by: 3654  \nCite this article: Yan, Renhong., Zhang, Yuanyuan., Li, Yaning., et al. **Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.** *Science (2020)*. doi:10.1126/science.abb2762\n\n### Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus.\n\nRecently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV's capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV. IMPORTANCE  The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.\n\nCited by: 2853  \nCite this article: Wan, Yushun., Shang, Jian., Graham, Rachel., et al. **Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus.** *J Virol (2020)*. doi:10.1128/JVI.00127-20\n\n### Structural basis of receptor recognition by SARS-CoV-2.\n\nA novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-19 1,2 . A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans 3,4 . Here we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.\n\nCited by: 2731  \nCite this article: Shang, Jian., Ye, Gang., Shi, Ke., et al. **Structural basis of receptor recognition by SARS-CoV-2.** *Nature (2020)*. doi:10.1038/s41586-020-2179-y\n\n### A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.\n\nDuring several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.\n\nCited by: 2521  \nCite this article: Kuba, Keiji., Imai, Yumiko., Rao, Shuan., et al. **A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.** *Nat Med (2005)*. doi:10.1038/nm1267\n\n### Cell entry mechanisms of SARS-CoV-2.\n\nA novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.\n\nCited by: 2397  \nCite this article: Shang, Jian., Wan, Yushun., Luo, Chuming., et al. **Cell entry mechanisms of SARS-CoV-2.** *Proc Natl Acad Sci U S A (2020)*. doi:10.1073/pnas.2003138117\n\n### A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.\n\nACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.\n\nCited by: 2327  \nCite this article: Donoghue, M., Hsieh, F., Baronas, E., et al. **A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.** *Circ Res (2000)*. doi:10.1161/01.res.87.5.e1\n\n### Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV.\n\nSince 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002-2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biology of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are critical for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients' sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.\n\nCited by: 2286  \nCite this article: Ou, Xiuyuan., Liu, Yan., Lei, Xiaobo., et al. **Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV.** *Nat Commun (2020)*. doi:10.1038/s41467-020-15562-9\n\n### The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.\n\nAn acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.\n\nCited by: 2254  \nCite this article: Guo, Yan-Rong., Cao, Qing-Dong., Hong, Zhong-Si., et al. **The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.** *Mil Med Res (2020)*. doi:10.1186/s40779-020-00240-0\n\n### Mechanisms of SARS-CoV-2 entry into cells.\n\nThe unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.\n\nCited by: 2234  \nCite this article: Jackson, Cody B., Farzan, Michael., Chen, Bing., et al. **Mechanisms of SARS-CoV-2 entry into cells.** *Nat Rev Mol Cell Biol (2022)*. doi:10.1038/s41580-021-00418-x\n\n### Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.\n\nOver the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoonotic viral outbreak. Here, we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent SARS-CoV-2, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells, and confirm that human ACE2 is the receptor for the recently emerging SARS-CoV-2.\n\nCited by: 2231  \nCite this article: Letko, Michael., Marzi, Andrea., Munster, Vincent. **Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.** *Nat Microbiol (2020)*. doi:10.1038/s41564-020-0688-y\n\n### Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.\n\nThe recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.\n\nCited by: 2207  \nCite this article: Wang, Qihui., Zhang, Yanfang., Wu, Lili., et al. **Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.** *Cell (2020)*. doi:10.1016/j.cell.2020.03.045\n\n### Extrapulmonary manifestations of COVID-19.\n\nAlthough COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.\n\nCited by: 2158  \nCite this article: Gupta, Aakriti., Madhavan, Mahesh V., Sehgal, Kartik., et al. **Extrapulmonary manifestations of COVID-19.** *Nat Med (2020)*. doi:10.1038/s41591-020-0968-3\n\n### COVID-19 and the cardiovascular system.\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia, while also causing acute myocardial injury and chronic damage to the cardiovascular system. Therefore, particular attention should be given to cardiovascular protection during treatment for COVID-19.\n\nCited by: 1966  \nCite this article: Zheng, Ying-Ying., Ma, Yi-Tong., Zhang, Jin-Ying., et al. **COVID-19 and the cardiovascular system.** *Nat Rev Cardiol (2020)*. doi:10.1038/s41569-020-0360-5"},{"role":"user","content":"Write a short summary for a biologists that summarizes what the studies say about the search.\nOutput in markdown, start with a title, use footnote formatting (e.g. [^1]) for citations.\nEnsure citation formatting of the summary uses markdown footnotes and consistent with the source material.\nNo footnotes in titles. Do not include a heading for references, just include footnotes."}],"timestamp":"2026-03-10T14:20:17.998352","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"},"deepdive_v1.ncbi_search":{"id":"56663260-9c54-41ce-a4ba-4eb1c4bf8e8d","key":"deepdive_v1.ncbi_search","value":"## Source Material\nHere are the abstracts of the top highly cited studies relevant to the search.\n\n### SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.\n\nThe recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.\n\nCited by: 14229  \nCite this article: Hoffmann, Markus., Kleine-Weber, Hannah., Schroeder, Simon., et al. **SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.** *Cell (2020)*. doi:10.1016/j.cell.2020.02.052\n\n### A pneumonia outbreak associated with a new coronavirus of probable bat origin.\n\nSince the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1-4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5-7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor-angiotensin converting enzyme II (ACE2)-as SARS-CoV.\n\nCited by: 13808  \nCite this article: Zhou, Peng., Yang, Xing-Lou., Wang, Xian-Guang., et al. **A pneumonia outbreak associated with a new coronavirus of probable bat origin.** *Nature (2020)*. doi:10.1038/s41586-020-2012-7\n\n### Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.\n\nThe outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryo-electron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.\n\nCited by: 6424  \nCite this article: Wrapp, Daniel., Wang, Nianshuang., Corbett, Kizzmekia S., et al. **Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.** *Science (2020)*. doi:10.1126/science.abb2507\n\n### Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.\n\nThe emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S 1 /S 2  subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.\n\nCited by: 6273  \nCite this article: Walls, Alexandra C., Park, Young-Jun., Tortorici, M Alejandra., et al. **Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.** *Cell (2020)*. doi:10.1016/j.cell.2020.02.058\n\n### Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.\n\nA new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world 1-3 . Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor 4 . Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses 1-3,5 . The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.\n\nCited by: 4501  \nCite this article: Lan, Jun., Ge, Jiwan., Yu, Jinfang., et al. **Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.** *Nature (2020)*. doi:10.1038/s41586-020-2180-5\n\n### Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.\n\nSpike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells. Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2), isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV.\n\nCited by: 4368  \nCite this article: Li, Wenhui., Moore, Michael J., Vasilieva, Natalya., et al. **Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.** *Nature (2003)*. doi:10.1038/nature02145\n\n### Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.\n\nSevere acute respiratory syndrome (SARS) is an acute infectious disease that spreads mainly via the respiratory route. A distinct coronavirus (SARS-CoV) has been identified as the aetiological agent of SARS. Recently, a metallopeptidase named angiotensin-converting enzyme 2 (ACE2) has been identified as the functional receptor for SARS-CoV. Although ACE2 mRNA is known to be present in virtually all organs, its protein expression is largely unknown. Since identifying the possible route of infection has major implications for understanding the pathogenesis and future treatment strategies for SARS, the present study investigated the localization of ACE2 protein in various human organs (oral and nasal mucosa, nasopharynx, lung, stomach, small intestine, colon, skin, lymph nodes, thymus, bone marrow, spleen, liver, kidney, and brain). The most remarkable finding was the surface expression of ACE2 protein on lung alveolar epithelial cells and enterocytes of the small intestine. Furthermore, ACE2 was present in arterial and venous endothelial cells and arterial smooth muscle cells in all organs studied. In conclusion, ACE2 is abundantly present in humans in the epithelia of the lung and small intestine, which might provide possible routes of entry for the SARS-CoV. This epithelial expression, together with the presence of ACE2 in vascular endothelium, also provides a first step in understanding the pathogenesis of the main SARS disease manifestations.\n\nCited by: 4023  \nCite this article: Hamming, I., Timens, W., Bulthuis, M L C., et al. **Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.** *J Pathol (2004)*. doi:10.1002/path.1570\n\n### Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.\n\nAngiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome-coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B 0 AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms, with a local resolution of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B 0 AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the molecular basis for coronavirus recognition and infection.\n\nCited by: 3654  \nCite this article: Yan, Renhong., Zhang, Yuanyuan., Li, Yaning., et al. **Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2.** *Science (2020)*. doi:10.1126/science.abb2762\n\n### Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus.\n\nRecently, a novel coronavirus (2019-nCoV) has emerged from Wuhan, China, causing symptoms in humans similar to those caused by severe acute respiratory syndrome coronavirus (SARS-CoV). Since the SARS-CoV outbreak in 2002, extensive structural analyses have revealed key atomic-level interactions between the SARS-CoV spike protein receptor-binding domain (RBD) and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. Here, we analyzed the potential receptor usage by 2019-nCoV, based on the rich knowledge about SARS-CoV and the newly released sequence of 2019-nCoV. First, the sequence of 2019-nCoV RBD, including its receptor-binding motif (RBM) that directly contacts ACE2, is similar to that of SARS-CoV, strongly suggesting that 2019-nCoV uses ACE2 as its receptor. Second, several critical residues in 2019-nCoV RBM (particularly Gln493) provide favorable interactions with human ACE2, consistent with 2019-nCoV's capacity for human cell infection. Third, several other critical residues in 2019-nCoV RBM (particularly Asn501) are compatible with, but not ideal for, binding human ACE2, suggesting that 2019-nCoV has acquired some capacity for human-to-human transmission. Last, while phylogenetic analysis indicates a bat origin of 2019-nCoV, 2019-nCoV also potentially recognizes ACE2 from a diversity of animal species (except mice and rats), implicating these animal species as possible intermediate hosts or animal models for 2019-nCoV infections. These analyses provide insights into the receptor usage, cell entry, host cell infectivity and animal origin of 2019-nCoV and may help epidemic surveillance and preventive measures against 2019-nCoV. IMPORTANCE  The recent emergence of Wuhan coronavirus (2019-nCoV) puts the world on alert. 2019-nCoV is reminiscent of the SARS-CoV outbreak in 2002 to 2003. Our decade-long structural studies on the receptor recognition by SARS-CoV have identified key interactions between SARS-CoV spike protein and its host receptor angiotensin-converting enzyme 2 (ACE2), which regulate both the cross-species and human-to-human transmissions of SARS-CoV. One of the goals of SARS-CoV research was to build an atomic-level iterative framework of virus-receptor interactions to facilitate epidemic surveillance, predict species-specific receptor usage, and identify potential animal hosts and animal models of viruses. Based on the sequence of 2019-nCoV spike protein, we apply this predictive framework to provide novel insights into the receptor usage and likely host range of 2019-nCoV. This study provides a robust test of this reiterative framework, providing the basic, translational, and public health research communities with predictive insights that may help study and battle this novel 2019-nCoV.\n\nCited by: 2853  \nCite this article: Wan, Yushun., Shang, Jian., Graham, Rachel., et al. **Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus.** *J Virol (2020)*. doi:10.1128/JVI.00127-20\n\n### Structural basis of receptor recognition by SARS-CoV-2.\n\nA novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-19 1,2 . A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans 3,4 . Here we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystallization) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Additionally, we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.\n\nCited by: 2731  \nCite this article: Shang, Jian., Ye, Gang., Shi, Ke., et al. **Structural basis of receptor recognition by SARS-CoV-2.** *Nature (2020)*. doi:10.1038/s41586-020-2179-y\n\n### A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.\n\nDuring several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.\n\nCited by: 2521  \nCite this article: Kuba, Keiji., Imai, Yumiko., Rao, Shuan., et al. **A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.** *Nat Med (2005)*. doi:10.1038/nm1267\n\n### Cell entry mechanisms of SARS-CoV-2.\n\nA novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) is causing the global coronavirus disease 2019 (COVID-19) pandemic. Understanding how SARS-CoV-2 enters human cells is a high priority for deciphering its mystery and curbing its spread. A virus surface spike protein mediates SARS-CoV-2 entry into cells. To fulfill its function, SARS-CoV-2 spike binds to its receptor human ACE2 (hACE2) through its receptor-binding domain (RBD) and is proteolytically activated by human proteases. Here we investigated receptor binding and protease activation of SARS-CoV-2 spike using biochemical and pseudovirus entry assays. Our findings have identified key cell entry mechanisms of SARS-CoV-2. First, SARS-CoV-2 RBD has higher hACE2 binding affinity than SARS-CoV RBD, supporting efficient cell entry. Second, paradoxically, the hACE2 binding affinity of the entire SARS-CoV-2 spike is comparable to or lower than that of SARS-CoV spike, suggesting that SARS-CoV-2 RBD, albeit more potent, is less exposed than SARS-CoV RBD. Third, unlike SARS-CoV, cell entry of SARS-CoV-2 is preactivated by proprotein convertase furin, reducing its dependence on target cell proteases for entry. The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike potentially allow SARS-CoV-2 to maintain efficient cell entry while evading immune surveillance. These features may contribute to the wide spread of the virus. Successful intervention strategies must target both the potency of SARS-CoV-2 and its evasiveness.\n\nCited by: 2397  \nCite this article: Shang, Jian., Wan, Yushun., Luo, Chuming., et al. **Cell entry mechanisms of SARS-CoV-2.** *Proc Natl Acad Sci U S A (2020)*. doi:10.1073/pnas.2003138117\n\n### A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.\n\nACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.\n\nCited by: 2327  \nCite this article: Donoghue, M., Hsieh, F., Baronas, E., et al. **A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.** *Circ Res (2000)*. doi:10.1161/01.res.87.5.e1\n\n### Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV.\n\nSince 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002-2003, MERS-CoV in 2012, and the newly emerged SARS-CoV-2 in late 2019. However, little is currently known about the biology of SARS-CoV-2. Here, using SARS-CoV-2 S protein pseudovirus system, we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are critical for entry, and that SARS-CoV-2 S protein is less stable than SARS-CoV S. Polyclonal anti-SARS S1 antibodies T62 inhibit entry of SARS-CoV S but not SARS-CoV-2 S pseudovirions. Further studies using recovered SARS and COVID-19 patients' sera show limited cross-neutralization, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for SARS-CoV-2.\n\nCited by: 2286  \nCite this article: Ou, Xiuyuan., Liu, Yan., Lei, Xiaobo., et al. **Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV.** *Nat Commun (2020)*. doi:10.1038/s41467-020-15562-9\n\n### The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.\n\nAn acute respiratory disease, caused by a novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV), the coronavirus disease 2019 (COVID-19) has spread throughout China and received worldwide attention. On 30 January 2020, World Health Organization (WHO) officially declared the COVID-19 epidemic as a public health emergency of international concern. The emergence of SARS-CoV-2, since the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, marked the third introduction of a highly pathogenic and large-scale epidemic coronavirus into the human population in the twenty-first century. As of 1 March 2020, a total of 87,137 confirmed cases globally, 79,968 confirmed in China and 7169 outside of China, with 2977 deaths (3.4%) had been reported by WHO. Meanwhile, several independent research groups have identified that SARS-CoV-2 belongs to β-coronavirus, with highly identical genome to bat coronavirus, pointing to bat as the natural host. The novel coronavirus uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that for SARS-CoV, and mainly spreads through the respiratory tract. Importantly, increasingly evidence showed sustained human-to-human transmission, along with many exported cases across the globe. The clinical symptoms of COVID-19 patients include fever, cough, fatigue and a small population of patients appeared gastrointestinal infection symptoms. The elderly and people with underlying diseases are susceptible to infection and prone to serious outcomes, which may be associated with acute respiratory distress syndrome (ARDS) and cytokine storm. Currently, there are few specific antiviral strategies, but several potent candidates of antivirals and repurposed drugs are under urgent investigation. In this review, we summarized the latest research progress of the epidemiology, pathogenesis, and clinical characteristics of COVID-19, and discussed the current treatment and scientific advancements to combat the epidemic novel coronavirus.\n\nCited by: 2254  \nCite this article: Guo, Yan-Rong., Cao, Qing-Dong., Hong, Zhong-Si., et al. **The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the status.** *Mil Med Res (2020)*. doi:10.1186/s40779-020-00240-0\n\n### Mechanisms of SARS-CoV-2 entry into cells.\n\nThe unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.\n\nCited by: 2234  \nCite this article: Jackson, Cody B., Farzan, Michael., Chen, Bing., et al. **Mechanisms of SARS-CoV-2 entry into cells.** *Nat Rev Mol Cell Biol (2022)*. doi:10.1038/s41580-021-00418-x\n\n### Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.\n\nOver the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoonotic viral outbreak. Here, we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent SARS-CoV-2, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells, and confirm that human ACE2 is the receptor for the recently emerging SARS-CoV-2.\n\nCited by: 2231  \nCite this article: Letko, Michael., Marzi, Andrea., Munster, Vincent. **Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses.** *Nat Microbiol (2020)*. doi:10.1038/s41564-020-0688-y\n\n### Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.\n\nThe recent emergence of a novel coronavirus (SARS-CoV-2) in China has caused significant public health concerns. Recently, ACE2 was reported as an entry receptor for SARS-CoV-2. In this study, we present the crystal structure of the C-terminal domain of SARS-CoV-2 (SARS-CoV-2-CTD) spike (S) protein in complex with human ACE2 (hACE2), which reveals a hACE2-binding mode similar overall to that observed for SARS-CoV. However, atomic details at the binding interface demonstrate that key residue substitutions in SARS-CoV-2-CTD slightly strengthen the interaction and lead to higher affinity for receptor binding than SARS-RBD. Additionally, a panel of murine monoclonal antibodies (mAbs) and polyclonal antibodies (pAbs) against SARS-CoV-S1/receptor-binding domain (RBD) were unable to interact with the SARS-CoV-2 S protein, indicating notable differences in antigenicity between SARS-CoV and SARS-CoV-2. These findings shed light on the viral pathogenesis and provide important structural information regarding development of therapeutic countermeasures against the emerging virus.\n\nCited by: 2207  \nCite this article: Wang, Qihui., Zhang, Yanfang., Wu, Lili., et al. **Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.** *Cell (2020)*. doi:10.1016/j.cell.2020.03.045\n\n### Extrapulmonary manifestations of COVID-19.\n\nAlthough COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.\n\nCited by: 2158  \nCite this article: Gupta, Aakriti., Madhavan, Mahesh V., Sehgal, Kartik., et al. **Extrapulmonary manifestations of COVID-19.** *Nat Med (2020)*. doi:10.1038/s41591-020-0968-3\n\n### COVID-19 and the cardiovascular system.\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia, while also causing acute myocardial injury and chronic damage to the cardiovascular system. Therefore, particular attention should be given to cardiovascular protection during treatment for COVID-19.\n\nCited by: 1966  \nCite this article: Zheng, Ying-Ying., Ma, Yi-Tong., Zhang, Jin-Ying., et al. **COVID-19 and the cardiovascular system.** *Nat Rev Cardiol (2020)*. doi:10.1038/s41569-020-0360-5","timestamp":"2026-03-10T14:20:17.99476","runnable_id":"ddea8fef-d9e7-47ec-a0cf-51465a8e7a2a"}},"num_comments":"0"}}}]