High affinity binding of SARS-CoV-2 spike protein enhances ACE2 carboxypeptidase activity
Jinghua Lu, Peter D. Sun
Abstract
The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19. The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19. The novel coronavirus, SARS-CoV-2 (1Wu F. Zhao S. Yu B. Chen Y.-M. Wang W. Song Z.-G. Hu Y. Tao Z.-W. Tian J.-H. Pei Y.-Y. Yuan M.-L. Zhang Y.-L. Dai F.-H. Liu Y. Wang Q.-M. et al.A new coronavirus associated with human respiratory disease in China.Nature. 2020; 579 (32015508): 265-26910.1038/s41586-020-2008-3Crossref PubMed Scopus (6424) Google Scholar, 2Zhou P. Yang X.-L. Wang X.-G. Hu B. Zhang L. Zhang W. Si H.-R. Zhu Y. Li B. Huang C.-L. Chen H.-D. Chen J. Luo Y. Guo H. Jiang R.-D. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579 (32015507): 270-27310.1038/s41586-020-2012-7Crossref PubMed Scopus (12486) Google Scholar, 3Zhu N. Zhang D. Wang W. Li X. Yang B. Song J. Zhao X. Huang B. Shi W. Lu R. Niu P. Zhan F. Ma X. Wang D. Xu W. China Novel Coronavirus Investigating and Research Team et al.A novel coronavirus from patients with pneumonia in China, 2019.N. Engl. J. 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Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581 (32225176): 215-22010.1038/s41586-020-2180-5Crossref PubMed Scopus (3256) Google Scholar, 12Shang J. Ye G. Shi K. Wan Y. Luo C. Aihara H. Geng Q. Auerbach A. Li F. Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581 (32225175): 221-22410.1038/s41586-020-2179-yCrossref PubMed Scopus (2176) Google Scholar, 13Wang Q. Zhang Y. Wu L. Niu S. Song C. Zhang Z. Lu G. Qiao C. Hu Y. Yuen K.-Y. Wang Q. Zhou H. Yan J. Qi J. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.Cell. 2020; 181 (e899) (32275855): 894-90410.1016/j.cell.2020.03.045Abstract Full Text Full Text PDF PubMed Scopus (1713) Google Scholar). The overall structure of SARS-CoV-2 S resembles that of SARS-CoV S with the spike RBD domain contacting the extracellular region of ACE2. Physiologically, ACE2 is a zinc metalloprotease (carboxypeptidase), a homolog to dipeptidase angiotensin-converting enzyme (ACE) but with different substrate specificity (14Vickers C. Hales P. Kaushik V. Dick L. Gavin J. Tang J. Godbout K. Parsons T. Baronas E. Hsieh F. Acton S. Patane M. Nichols A. Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.J. Biol. Chem. 2002; 277 (11815627): 14838-1484310.1074/jbc.M200581200Abstract Full Text Full Text PDF PubMed Scopus (1143) Google Scholar). ACE cleaves the C-terminal of angiotensin I (Ang I) to produce the potent vasopressor octapeptide angiotensin II (Ang II), which is further cleaved at its C terminus by ACE2 to deactivate Ang II and produce Ang 1-7. Together, ACE and ACE2 regulate vasoconstriction and vasodilatation in the rennin-angiotensin system (RAS). In addition, ACE and ACE2 regulate kinin-kallikrein system to control vascular permeability and vasodilatation (15Kaplan A.P. Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway.Adv. Immunol. 2014; 121 (24388213): 41-8910.1016/B978-0-12-800100-4.00002-7Crossref PubMed Scopus (89) Google Scholar). ACE deactivates Bradykinin (BK) nonapeptide, the ligand for constitutively expressed bradykinin receptor B2. Bradykinin can be further processed by carboxypeptidase N or M to form des-Arg9-bradykinin (desBK), a potent ligand for bradykinin receptor B1(16van de Veerdonk F.L. Netea M.G. van Deuren M. van der de Q. van der H. in patients with COVID-19 to acute respiratory distress 2020; PubMed Google Scholar). and kinin-kallikrein ACE2 cleaves biological peptides such as that receptor to vasodilatation P. et a ACE2 of the 11 Google Scholar). the of ACE2 in is understanding to the of coronavirus infection to the function of ACE2. ACE2 is expressed II in lung K. T. T. Chen G. A. et a in the 2020; Full Text Full Text PDF PubMed Scopus Google Scholar). that COVID-19 patients and of fluid in lung (7Kuba K. Imai Y. Rao S. Gao H. Guo F. Guan B. Huan Y. Yang P. Zhang Y. Deng W. Bao L. Zhang B. Liu G. Wang Z. Chappell M. et al.A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.Nat. Med. 2005; 11 (16007097): 875-87910.1038/nm1267Crossref PubMed Scopus (2395) Google Scholar, de Veerdonk F.L. Netea M.G. van Deuren M. van der de Q. van der H. in patients with COVID-19 to acute respiratory distress 2020; PubMed Google Scholar, Y. K. Rao S. Huan Y. Guo F. Guan B. Yang P. R. T. H. M.A. A. L. S. et enzyme 2 from severe acute lung 2005; PubMed Scopus Google Scholar), a by in vascular permeability and vasodilatation SARS-CoV-2 However, was of ACE2 enzymatic activity the coronavirus we the of the binding of SARS-CoV-2 spike protein to the enzymatic activity of ACE2 substrates, the caspase-1 substrate (14Vickers C. Hales P. Kaushik V. Dick L. Gavin J. Tang J. Godbout K. Parsons T. Baronas E. Hsieh F. Acton S. Patane M. Nichols A. Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.J. Biol. Chem. 2002; 277 (11815627): 14838-1484310.1074/jbc.M200581200Abstract Full Text Full Text PDF PubMed Scopus (1143) Google Scholar), and a bradykinin K. of an substrate for PubMed Scopus Google Scholar). SARS-CoV-2 spike ACE2 proteolytic activity both caspase-1 substrate and and the enzymatic enhancement was mediated by the spike RBD domain The of SARS-CoV-2 spike protein to ACE2 enzymatic activity may in dysregulation of and to the of COVID-19. SARS-CoV-2 is to SARS-CoV and both ACE2 as entry receptor P. Yang X.-L. Wang X.-G. Hu B. Zhang L. Zhang W. Si H.-R. Zhu Y. Li B. Huang C.-L. Chen H.-D. Chen J. Luo Y. Guo H. Jiang R.-D. et al.A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature. 2020; 579 (32015507): 270-27310.1038/s41586-020-2012-7Crossref PubMed Scopus (12486) Google Scholar, 9Li W. Moore M.J. Vasilieva N. Sui J. Wong S.K. Berne M.A. Somasundaran M. Sullivan J.L. Luzuriaga K. Greenough T.C. Choe H. Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426 (14647384): 450-45410.1038/nature02145Crossref PubMed Scopus (4100) Google Scholar). studies that both SARS-CoV-2 and SARS-CoV spike protein RBD domain to with ACE2 in binding J. Ge J. Yu J. Shan S. Zhou H. Fan S. Zhang Q. Shi X. Wang Q. Zhang L. Wang X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581 (32225176): 215-22010.1038/s41586-020-2180-5Crossref PubMed Scopus (3256) Google Scholar). However, SARS-CoV-2 spike protein higher binding affinity to ACE2 than that of Given the nanomolar affinity between ACE2 and SARS-CoV-2 S spike protein, we the binding of SARS-CoV-2 spike protein to ACE2 its function as a carboxypeptidase both the rennin-angiotensin and kinin-kallikrein (15Kaplan A.P. Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway.Adv. Immunol. 2014; 121 (24388213): 41-8910.1016/B978-0-12-800100-4.00002-7Crossref PubMed Scopus (89) Google Scholar, C. a new of the Full Text Full Text PDF PubMed Scopus Google Scholar). As ACE2 peptides with between and the as by Ang II and (14Vickers C. Hales P. Kaushik V. Dick L. Gavin J. Tang J. Godbout K. Parsons T. Baronas E. Hsieh F. Acton S. Patane M. Nichols A. Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.J. Biol. Chem. 2002; 277 (11815627): 14838-1484310.1074/jbc.M200581200Abstract Full Text Full Text PDF PubMed Scopus (1143) Google Scholar). ACE2 cleaves peptides with a at such as and ACE2 proteolytic activity substrate (14Vickers C. Hales P. Kaushik V. Dick L. Gavin J. Tang J. Godbout K. Parsons T. Baronas E. Hsieh F. Acton S. Patane M. Nichols A. Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.J. Biol. Chem. 2002; 277 (11815627): 14838-1484310.1074/jbc.M200581200Abstract Full Text Full Text PDF PubMed Scopus (1143) Google Scholar), and bradykinin K. of an substrate for PubMed Scopus Google Scholar). ACE2 but cleaved bradykinin and 2 ACE2 cleaved of and of Surprisingly, of SARS-CoV-2 spike protein at to the enzymatic in fold in ACE2 of both the caspase-1 substrate and the and with ACE2 activity (14Vickers C. Hales P. Kaushik V. Dick L. Gavin J. Tang J. Godbout K. Parsons T. Baronas E. Hsieh F. Acton S. Patane M. Nichols A. Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.J. Biol. Chem. 2002; 277 (11815627): 14838-1484310.1074/jbc.M200581200Abstract Full Text Full Text PDF PubMed Scopus (1143) Google Scholar), SARS-CoV-2 spike protein further ACE2 of both peptides at and the enhancement was by the interaction between SARS-CoV-2 spike protein and ACE2. In addition, the spike enhancement of ACE2 activity the of the of SARS-CoV-2 spike protein from to the enhancement to ACE2 activity with a between and of SARS-CoV-2 spike protein and enhancement of ACE2 activity was with a binding affinity between ACE2 and SARS-CoV-2 spike protein studies that SARS-CoV infection may to of ACE2 receptor and of ACE2 (7Kuba K. Imai Y. Rao S. Gao H. Guo F. Guan B. Huan Y. Yang P. Zhang Y. Deng W. Bao L. Zhang B. Liu G. Wang Z. Chappell M. et al.A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.Nat. Med. 2005; 11 (16007097): 875-87910.1038/nm1267Crossref PubMed Scopus (2395) Google Scholar). However, of SARS-CoV-2 infected ACE2 transgenic lung of the spike and ACE2 receptor infection L. et al.The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.Natjure. 2020; Google Scholar, K. T. T. Chen G. A. et a in the 2020; Full Text Full Text PDF PubMed Scopus Google Scholar), the of a the of infected SARS-CoV-2 and SARS-CoV spike protein in prefusion trimeric and both bind ACE2 with receptor binding domain RBD domain was to ACE2 both SARS-CoV-2 RBD and SARS-CoV RBD ACE2 of caspase-1 substrate and that RBD was to enhance ACE2 However, SARS-CoV-2 spike protein higher ACE2 binding affinity than SARS-CoV (10Wrapp D. Wang N. Corbett K.S. Goldsmith J.A. Hsieh C.-L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.Science. 2020; 367 (32075877): 1260-126310.1126/science.abb2507Crossref PubMed Scopus (74) Google Scholar, 12Shang J. Ye G. Shi K. Wan Y. Luo C. Aihara H. Geng Q. Auerbach A. Li F. Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581 (32225175): 221-22410.1038/s41586-020-2179-yCrossref PubMed Scopus (2176) Google Scholar). The enhancement of ACE2 activity by SARS-CoV-2 RBD a with at the enhancement by SARS-CoV RBD was with the RBD with enhancement at SARS-CoV-2 RBD but SARS-CoV RBD ACE2 of the and SARS-CoV-2 RBD bound to ACE2 at nanomolar fold than that of SARS-CoV RBD J. Ye G. Shi K. Wan Y. Luo C. Aihara H. Geng Q. Auerbach A. Li F. Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581 (32225175): 221-22410.1038/s41586-020-2179-yCrossref PubMed Scopus (2176) Google Scholar). The different of SARS-CoV-2 and SARS-CoV RBD to enhance ACE2 enzymatic activity that the interaction between RBD and ACE2 is for its of substrates such as bradykinin the spike enhancement is to carboxypeptidase activity of ACE2 than potential in the spike as the enzymatic enhancement was in the of a potent ACE2 and In of the for and ACE2 at its enhancement by the spike RBD the spike RBD ACE2 carboxypeptidase and ACE2 ACE2 activity and the enhancement mediated by SARS-CoV-2 spike and RBD protein at ACE2 further how ACE2 cleaves caspase-1 substrate and bradykinin in the of SARS-CoV-2 spike protein, we the of ACE2 with The were with ACE2 in the or of SARS-CoV-2 spike protein, and the was to as that SARS-CoV-2 spike protein in a in binding from to for ACE2 of the and SARS-CoV-2 spike protein the for ACE2 of from to results in a and to for ACE2 of the caspase-1 substrate and is that for ACE2 of bradykinin in the of SARS-CoV-2 spike protein was to that of ACE2 of I a biological substrate for SARS-CoV-2 increased the substrate binding and of for of peptides and by ACE2 in the of SARS-CoV-2 spike protein for in a new SARS-CoV-2 spike protein ACE2 of caspase-1 substrate and was the spike binding ACE2 of its substrates and Ang of the to to the enzymatic we an substrate to the of the spike RBD binding ACE2 of caspase-1 substrate in the of or Ang II In the of SARS-CoV-2 RBD Ang II but the of caspase-1 substrate with an of with observed ACE2 binding to Ang II than to (14Vickers C. Hales P. Kaushik V. Dick L. Gavin J. Tang J. Godbout K. Parsons T. Baronas E. Hsieh F. Acton S. Patane M. Nichols A. Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.J. Biol. Chem. 2002; 277 (11815627): 14838-1484310.1074/jbc.M200581200Abstract Full Text Full Text PDF PubMed Scopus (1143) Google Scholar). In the of SARS-CoV-2 the ACE2 with a of that SARS-CoV-2 ACE2 binding to Surprisingly, ACE2 of (14Vickers C. Hales P. Kaushik V. Dick L. Gavin J. Tang J. Godbout K. Parsons T. Baronas E. Hsieh F. Acton S. Patane M. Nichols A. Tummino P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase.J. Biol. Chem. 2002; 277 (11815627): 14838-1484310.1074/jbc.M200581200Abstract Full Text Full Text PDF PubMed Scopus (1143) Google Scholar), ACE2 of caspase-1 substrate in the of the spike RBD with a of As for ACE2 of the Ang II with a of and in the and of the SARS-CoV-2 to that of caspase-1 substrate However, both and to ACE2 of As bound to converting than of its C-terminal K. of an substrate for PubMed Scopus Google Scholar). is that bound to ACE2 than The new coronavirus SARS-CoV-2 human the binding of its spike (S) to the human angiotensin-converting we the of the high affinity binding of SARS-CoV-2 spike protein the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 spike protein the enzymatic activity of ACE2 to caspase-1 peptide in a and RBD is that the spike protein binding to ACE2 would to more of substrates such as Ang II and the binding of SARS-CoV-2 spike ACE2 of bradykinin and bradykinin and des-Arg9-bradykinin for ACE2 of the caspase-1 further how the binding of the spike protein the activity of we of ACE2 in the and of the spike The structure of ACE2 extracellular proteolytic domain the and C-terminal with a in between for substrate binding and P. et a for binding and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google The structure of ACE2 with a potent bound at the a between the and C-terminal of ACE2 proteolytic domain binding was with that of ACE bound to its Ang II G. recognition and of human converting enzyme (ACE) activity by 2 PubMed Scopus Google Scholar), a to bind substrate and zinc The between and bound ACE2 revealed a substrate binding and SARS-CoV-2 and SARS-CoV spike protein both the receptor binding domain to ACE2 domain J. Ge J. Yu J. Shan S. Zhou H. Fan S. Zhang Q. Shi X. Wang Q. Zhang L. Wang X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor.Nature. 2020; 581 (32225176): 215-22010.1038/s41586-020-2180-5Crossref PubMed Scopus (3256) Google Scholar, 12Shang J. Ye G. Shi K. Wan Y. Luo C. Aihara H. Geng Q. Auerbach A. Li F. Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581 (32225175): 221-22410.1038/s41586-020-2179-yCrossref PubMed Scopus (2176) Google Scholar, 13Wang Q. Zhang Y. Wu L. Niu S. Song C. Zhang Z. Lu G. Qiao C. Hu Y. Yuen K.-Y. Wang Q. Zhou H. Yan J. Qi J. Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.Cell. 2020; 181 (e899) (32275855): 894-90410.1016/j.cell.2020.03.045Abstract Full Text Full Text PDF PubMed Scopus (1713) Google Scholar, F. Li W. Farzan M. Structure of SARS coronavirus spike receptor-binding domain with 2005; PubMed Scopus Google Scholar, W. M. Wang X. Y. Cryo-EM structure of the SARS coronavirus spike in with its receptor PubMed Scopus Google Scholar). The between RBD bound ACE2 and ACE2 revealed a in the of ACE2 with than and However, the SARS-CoV-2 RBD but SARS-CoV RBD binding caused the between the and C-terminal of a such by the by the of ACE2 C-terminal zinc at the and of ACE2 bound by RBD of SARS-CoV-2 or with SARS-CoV RBD binding this SARS-CoV-2 RBD binding was increased to the binding of a SARS-CoV-2 RBD to ACE2 J. Ye G. Shi K. Wan Y. Luo C. Aihara H. Geng Q. Auerbach A. Li F. Structural basis of receptor recognition by SARS-CoV-2.Nature. 2020; 581 (32225175): 221-22410.1038/s41586-020-2179-yCrossref PubMed Scopus (2176) Google Scholar), in a of ACE2 C-terminal domain the domain this was resulting in a of ACE2 in the of that SARS-CoV-2 spike binding a to ACE2 The of substrate binding ACE2 that and in to Ang II or with the RBD binding the substrate binding is with a in of ACE2 in the of SARS-CoV-2 spike In addition, in SARS-CoV-2 RBD bound that was to the the as that bound by of was observed in or SARS-CoV RBD bound ACE2 that the binding of SARS-CoV-2 RBD a to ACE2 substrate for of confirmed cases the of SARS-CoV-2 mediated COVID-19 disease and its complications of the of or with SARS-CoV and SARS-CoV-2 is more and the symptoms of COVID-19 (4Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Cheng Z. Yu T. Xia J. Wei Y. Wu W. et al.Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020; 395: 497-50610.1016/S0140-6736(20)30183-5Abstract Full Text Full Text PDF PubMed Scopus (28324) Google Scholar). In to the of fluid in the a of COVID-19 patients venous or (6Wichmann D. et al.Autopsy findings and venous thromboembolism in patients with COVID-19.Ann. Intern. Med. 2020; 173: 268-277Crossref PubMed Scopus (1490) Google Scholar). These a that to the cardiovascular and permeability the of the cardiovascular which by the of many and biological system and kinin-kallikrein system have cardiovascular function (15Kaplan A.P. Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway.Adv. Immunol. 2014; 121 (24388213): 41-8910.1016/B978-0-12-800100-4.00002-7Crossref PubMed Scopus (89) Google Scholar, C. a new of the Full Text Full Text PDF PubMed Scopus Google Scholar). ACE2 the of peptides in to the the biological substrates, ACE2 cleaves Ang II and with high proteolytic and ACE2 has activity against des-Arg9-bradykinin and results that SARS-CoV-2 may ACE2 of substrates in infected SARS-CoV-2 the enhancement of ACE2 activity produce more of cleaved Ang and Ang 1-7. the of Ang II and Ang vasoconstriction and the of ACE2. in and in studies that Ang II ACE2 of Ang increased the receptor J. S. S. angiotensin in and 2014; PubMed Scopus Google Scholar, the of ACE2 by angiotensin J. PubMed Scopus Google Scholar). ACE2 was increased in the lungs of severe COVID-19 patients with with control individuals K. T. T. Chen G. A. et a in the 2020; Full Text Full Text PDF PubMed Scopus Google Scholar, et is in the of with with 2020; Scholar). is with the binding of the spike protein resulting in ACE2 of Ang is an ligand for angiotensin II protein receptor a homolog of the angiotensin receptor W. M. M. T. B. C. S. Angiotensin-converting enzyme 2 and and in the cardiovascular PubMed Scopus Google Scholar). to to Ang II The of its interaction with Y. Y. Ma Y. Zhang Q. Zhou Q. Song Y. Y. Li X. Ma X. Li C. M.A. G. Zhao S. et basis for control of the human Full Text Full Text PDF PubMed Scopus Google Scholar), resulting in to of its P. et a ACE2 of the 11 Google Scholar). The enhancement of ACE2 activity would the of further its to The of bradykinin may be relevant to COVID-19 as ACE2 des-Arg9-bradykinin (15Kaplan A.P. Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway.Adv. Immunol. 2014; 121 (24388213): 41-8910.1016/B978-0-12-800100-4.00002-7Crossref PubMed Scopus (89) Google Scholar). The spike ACE2 activity may affect of des-Arg9-bradykinin A.P. The of of bradykinin in human Biol. Scopus Google Scholar). The ACE2 of bradykinin in the of SARS-CoV-2 RBD the increased ACE2 activity SARS-CoV-2 spike binding may of and in In to vascular COVID-19 patients with and of and The and ACE2 which for and have or Full Text Full Text PDF PubMed Scopus Google Scholar). was as an C. E. role for and in the control of PubMed Scopus Google Scholar). The of the C-terminal of in of its C. A. receptor for the peptide S A. PubMed Scopus Google Scholar). is to that ACE2 of would affect the of as The of and or the understanding SARS-CoV-2 infection to the of COVID-19 the of SARS-CoV-2 spike protein the enzymatic activity of ACE2 and further the biological of ACE2 in individuals infected with SARS-CoV-2. Given the role of ACE2 in the of cardiovascular that ACE2 activity may of the vascular complications associated with COVID-19 studies of and COVID-19 patients be to the of this spike ACE2 of human ACE2 extracellular enzymatic domain with were from and of SARS-CoV RBD and SARS-CoV-2 RBD were from peptide substrates were from was as an angiotensin II substrate and was a peptide of Bradykinin to des-Arg9-bradykinin and angiotensin II (Ang peptides were from ACE2 and and were from peptide was as to the to The to the prefusion S a of was by S. McLellan of at and the protein was expressed as (10Wrapp D. Wang N. Corbett K.S. Goldsmith J.A. Hsieh C.-L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation.Science. 2020; 367 (32075877): 1260-126310.1126/science.abb2507Crossref PubMed Scopus (74) Google Scholar). In were with this was from and to further by a with the of enzymatic SARS-CoV-2 spike and RBD were against and were a and with Human ACE2 was to a in The of of SARS-CoV-2 spike protein between and in a and The were by with binding model were in at to of or ACE2 in at or were or SARS-CoV-2 S domain at from to were to and for by The were by of peptides at or with from to to the for ACE2 The were at and of and in at for activity of the substrate were to to the that was by the the was to as the were substrate and to the were from the a ACE2 of and the enzyme to be and the proteolytic activity of ACE2 with different substrates, of or Ang II peptides were to the with peptides as As of ACE2 at was with or SARS-CoV-2 RBD protein at a of for of peptides at with a of or Ang II peptides to were to enzymatic In addition, of ACE2 was as control to ACE2 activity in the or of SARS-CoV-2 SARS-CoV-2 or SARS-CoV RBD at a of such as and were to the activity of ACE2 were at 1 for 1 at as the The was with a model to was to the in was at with was in the the and can be for the with diffuse alveolar damage angiotensin-converting enzyme rennin-angiotensin system Bradykinin receptor binding domain converting