Biology:Angiotensin-converting enzyme 2

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Short description: Exopeptidase enzyme that acts on angiotensin I and II
"ACE2" redirects here. For other uses, see Ace 2 (disambiguation).

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Angiotensin-converting enzyme 2 (ACE2)[1] is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines, kidney, testis, gallbladder, and heart or in a soluble form (sACE2).[2][3][4] Both membrane bound and soluble ACE2 are integral parts of the renin–angiotensin–aldosterone system (RAAS) that exists to keep the body's blood pressure in check. mACE2 is cleaved by the enzyme ADAM17 in a process regulated by substrate presentation. ADAM17 cleavage releases the extracellular domain creating soluble ACE2 (sACE2).[5] ACE2 enzyme activity opposes the classical arm of the RAAS by lowering blood pressure through catalyzing the hydrolysis of angiotensin II (a vasoconstrictor peptide which raises blood pressure) into angiotensin (1–7) (a vasodilator).[4][6][7] Angiotensin (1-7) in turns binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure.[8] This decrease in blood pressure makes the entire process a promising drug target for treating cardiovascular diseases.[9][10]

mACE2 (Membrane-bound angiotensin-converting enzyme 2) also serves as the entry point into cells for some coronaviruses, including HCoV-NL63, SARS-CoV, and SARS-CoV-2.[1] While mACE2's function is not that of a biological receptor, because of its receptor-like interaction with viruses it is also referred to as the ACE2 receptor.[11] The human version of the enzyme can be referred to as hACE2.[12]

Tissue distribution

mACE2 is attached to the cell membrane of mainly enterocytes of the small intestine and duodenum, proximal tubular cells of the kidneys, glandular cells of the gallbladder, as well as Sertoli cells and Leydig cells of the testis.[2] The expression profile of mACE2 in the human body was recently thoroughly evaluated by the Human Protein Atlas team using a large-scale multiomics approach combining several different methods for analysis of gene expression, including a stringent immunohistochemical analysis using two independent antibodies.[2][13] In addition to the above-mentioned issues, mACE2 expression was also seen in endothelial cells and pericytes of blood vessels within certain tissues, cardiomyocytes in heart tissue, and a smaller subset of cells within the thyroid gland, epididymis, seminal vesicle, pancreas, liver and placenta. Despite the fact that the respiratory system is the primary route of SARS-CoV-2 infection, very limited expression is seen, both at protein and mRNA level. The expression within the respiratory system is mainly restricted to the upper bronchial and nasal epithelia, especially in the ciliated cells.[14]

Structure

Angiotensin-converting enzyme 2
Identifiers
EC number3.4.17.23
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum

Membrane bound angiotensin-converting enzyme 2 (mACE2) is a zinc-containing metalloenzyme located on the surface of intestinal enterocytes, renal tubular cells and other cells.[2][15] mACE2 protein contains an N-terminal peptidase M2 domain and a C-terminal collectrin renal amino acid transporter domain.[15]

mACE2 is a single-pass type I membrane protein, with its enzymatically active domain exposed on the surface of cells in the intestines and other tissues.[2][3] The extracellular domain of mACE2 can be cleaved from the transmembrane domain by another enzyme known as ADAM17 a member of the sheddase enzyme family, during the protective phase of RAAS, the Renin–Angiotensin–Aldosterone System, which regulates our body's blood pressure. The resulting cleaved protein is known as soluble ACE2 or sACE2. It is released into the bloodstream where one of sACE2's functions is to turn excess angiotensin II into angiotensin 1-7 which binds to MasR receptors creating localized vasodilation and hence decreasing blood pressure. Excess sACE2 may ultimately be excreted in the urine.[16][17]

Function

As part of the renin–angiotensin–aldosterone system (RAAS) protective phase, soluble ACE2's (sACE2) important function is to act as a counterbalance to the angiotensin-converting enzyme (ACE). ACE cleaves angiotensin I hormone into the vasoconstricting angiotensin II which causes a cascade of hormonal reactions which is part of the body's harmful phase of RAAS, which ultimately leads to an increase in the body's blood pressure. ACE2 has an opposing effect to ACE, degrading angiotensin II into angiotensin (1-7), thereby lowering blood pressure.[18][19]

sACE2, as part of RAAS's protective phase, cleaves the carboxyl-terminal amino acid phenylalanine from angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe) and hydrolyses it into the vasodilator angiotensin (1-7) (H-Asp-Arg-Val-Tyr-Ile-His-Pro-OH), which binds to Mas Receptors and ultimately leads to a decrease in blood pressure.[20][15] sACE2 can also cleave numerous peptides, including [des-Arg9]-bradykinin, apelin, neurotensin, dynorphin A, and ghrelin.[15]

mACE2 also regulates the membrane trafficking of the neutral amino acid transporter SLC6A19 and has been implicated in Hartnup's disease.[21][22][23]

Research in mice has shown that ACE2 (whether it is the membrane bound version or soluble is inconclusive) is involved in regulation of the blood glucose level but its mechanism is yet to be confirmed.[24][25]

Clinical significance

Coronavirus entry point

As a transmembrane protein, mACE2 is the main entry receptor for several coronaviruses, including HCoV-NL63,[1] SARS-CoV (the cause of SARS),[26][27][28] and SARS-CoV-2 (the cause of COVID-19).[29][30][31][32][33][34] The binding of the S1 site of the viral spike protein to the enzymatic domain of mACE2 on host cells initiates endocytosis and translocation of both virus and enzyme into endosomes.[35][36] Blocking endocytosis in culture traps virus particles on the cell surface.[37] The spike protein itself can also damage the endothelium through downregulation of ACE2.[38] The receptor-binding domain (RBD) of the spike protein specifically attaches to ACE2, enabling viral entry and replication,[34] while surfactant proteins SP-A and SP-D may reduce the strength of this interaction.[34]

Binding of SARS-CoV and SARS-CoV-2 through mACE2 in cardiac tissue has been linked to myocarditis which is inflammation of the heart muscle.[39] During the SARS outbreak, viral RNA was detected in heart specimens from 35% of fatal cases,[40] and diseased hearts express higher levels of mACE2 than healthy hearts.[41] Entry also requires priming of the spike protein by host serine protease TMPRSS2, a potential therapeutic target,[42][14] and disruption of spike glycosylation strongly impairs viral entry.[43] In mice, spike binding reduces mACE2 through internalization and degradation, contributing to lung injury.[44][45] By contrast, sACE2 protects against lung injury by promoting formation of angiotensin 1–7, a vasodilator, and may also neutralize coronavirus spikes by binding them.[33] Even low mACE2 levels can allow entry if TMPRSS2 is present.[46]

Rodent studies have shown that ACE inhibitors and angiotensin II receptor blockers (ARBs) upregulate mACE2, raising concern they might worsen infections.[47][48] However, a 2012 systematic review and meta-analysis found ACE inhibitors reduced pneumonia risk by 34% and lowered pneumonia-related mortality.[49] A 2020 study in Hubei Province reported lower mortality in hypertensive COVID-19 patients taking ACE inhibitors or ARBs (3.7%) compared to those not taking them (9.8%).[50] Despite debate over discontinuation,[51] professional societies recommend continuing ACE inhibitors and ARBs in COVID-19 patients.[52][53][54] High plasma ACE2 levels predict worse COVID-19 outcomes, and are elevated in patients with hypertension and heart disease.[55]

Because ACE2 is the entry receptor for SARS-CoV-2, genetic variation may influence susceptibility to infection. Several studies report that ACE2 missense variants alter spike-binding affinity[56][57][58] and susceptibility to pseudovirus entry.[59] Rare variants may even confer complete resistance.[58] Expression levels of ACE2 at the cell surface also influence susceptibility and tissue tropism,[59][60] since SARS-CoV-2 distribution depends on ACE2 expression across tissues.[61] A variant on the X chromosome (rs190509934:C) lowers ACE2 expression by 37% and has been associated with protection against severe COVID-19 outcomes.[62]

Recombinant ACE2

Recombinant human ACE2 (rhACE2) is being developed as an enzymatically active, soluble "decoy" that both binds the SARS-CoV-2 spike protein to block cell entry and converts angiotensin II to angiotensin-(1–7), thereby rebalancing the renin–angiotensin system. This dual mechanism underpins its proposed use in viral pneumonias and lung or vascular injury.[63][64] In humans, rhACE2 has a half-life of ~10 hours, an onset of action of about 30 minutes, and a duration of ~24 hours,[65] and may be useful for patients intolerant to classic RAS inhibitors or in conditions with elevated circulating angiotensin II.[65]

Preclinical studies have demonstrated protective effects in lung injury. In a piglet model of lipopolysaccharide-induced acute respiratory distress syndrome (ARDS), rhACE2 improved pulmonary blood flow and oxygenation.[65] Clinical-grade human recombinant soluble ACE2 (hrsACE2) also reduced SARS-CoV-2 recovery from vero cells by 1,000–5,000-fold in vitro, whereas the mouse ortholog had no such effect, consistent with a decoy mechanism.[66] Engineered ACE2 mutants with enhanced affinity for the viral Spike protein neutralised SARS-CoV-2 in vitro,[67] and a triple-mutant (sACE2.v2.4) with nanomolar Spike binding[67] blocked pseudovirus entry in lung cell lines and prevented SARS-CoV-2–induced ARDS in ACE2-humanized mice.[68] Novel formats such as Fc-fusions, multimers, and affinity-enhanced constructs are being designed to prolong half-life and broaden neutralization against immune-evasive variants, positioning ACE2 decoys as a potentially variant-agnostic antiviral strategy.[64]

Clinically, intravenous rhACE2 (also termed APN01/GSK2586881) has been tested in ARDS,[69] pulmonary arterial hypertension (PAH), and severe COVID-19, including studies of nebulized or inhaled formulations for direct airway exposure.[64][70] Early trials showed acceptable safety and pharmacodynamic changes (decreased Ang II, increased Ang-(1–7)), and the agent progressed to phase II testing in COVID-19.[71] Nonetheless, reviews emphasize that clinical efficacy remains unproven, and further randomized studies are needed to clarify optimal dosing, delivery routes, and whether catalytic activity should be preserved versus "decoy-only" constructs.[64] Overall, rhACE2 and next-generation ACE2 decoys remain promising host-targeted therapeutics, particularly as monoclonal antibody antivirals lose potency against new SARS-CoV-2 variants.[63]

See also

References

  1. ↑ 1.0 1.1 1.2 "Gene: ACE2, angiotensin I converting enzyme 2". National Center for Biotechnology Information (NCBI). U.S. National Library of Medicine. 2020-02-28. https://www.ncbi.nlm.nih.gov/gene/59272. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "The protein expression profile of ACE2 in human tissues". Molecular Systems Biology 16 (7). July 2020. doi:10.15252/msb.20209610. PMID 32715618. 
  3. ↑ 3.0 3.1 "Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis". The Journal of Pathology 203 (2): 631–637. June 2004. doi:10.1002/path.1570. PMID 15141377. 
  4. ↑ 4.0 4.1 "A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9". Circulation Research 87 (5): E1–E9. September 2000. doi:10.1161/01.RES.87.5.e1. PMID 10969042. 
  5. ↑ "Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)". The Journal of Biological Chemistry 280 (34): 30113–30119. August 2005. doi:10.1074/jbc.M505111200. PMID 15983030. 
  6. ↑ "ACE2 of the heart: From angiotensin I to angiotensin (1-7)". Cardiovascular Research 73 (3): 463–469. February 2007. doi:10.1016/j.cardiores.2006.09.006. PMID 17049503. 
  7. ↑ "Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System". Hypertension 68 (2): 365–377. August 2016. doi:10.1161/HYPERTENSIONAHA.115.06892. PMID 27217402. 
  8. ↑ "Angiotensin-converting enzyme 2 as a therapeutic target for heart failure". Current Heart Failure Reports (Springer Science and Business Media LLC) 11 (1): 58–63. March 2014. doi:10.1007/s11897-013-0178-0. PMID 24293035. "The discovery of ACE2 and its role in counteracting the effect of Ang-II through Ang(1-7) formation ... An imbalance in ACE2/Ang-(1–7) and ACE/Ang-II axes is critical in the development of cardiovascular diseases. The central role of ACE2, therefore, appears to counter ACE activity by reducing Ang-II bioavailability and increasing Ang(1-7) formation ... The use of RAS-modulating agents and molecules as novel therapeutic agents in hypertension and cardiovascular therapeutic research.". 
  9. ↑ "Angiotensin-converting enzyme 2 as a therapeutic target for heart failure". Current Heart Failure Reports (Springer Science and Business Media LLC) 11 (1): 58–63. March 2014. doi:10.1007/s11897-013-0178-0. PMID 24293035. "Studies with recombinant human ACE2 (rhACE2) have shown beneficial cardiac effects [18, 36]. rhACE2 has anti-fibrotic properties and can attenuate effect on systolic and diastolic dysfunction, presumably via Ang-II inhibition.". 
  10. ↑ "Angiotensin II and angiotensin 1-7: which is their role in atrial fibrillation?". Heart Failure Reviews (Springer Science and Business Media LLC) 25 (2): 367–380. March 2020. doi:10.1007/s10741-019-09837-7. PMID 31375968. http://openaccess.sgul.ac.uk/111404/1/Manuscript%20Ang-AF.docx. "the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.". 
  11. ↑ "What is the ACE2 receptor?" (in en). https://www.asbmb.org/asbmb-today/science/051620/what-is-the-ace2-receptor. 
  12. ↑ "Coronaviridae: 100,000 Years of Emergence and Reemergence". Emerging and Reemerging Viral Pathogens: Fundamental and Basic Virology Aspects of Human, Animal and Plant Pathogens. 1. Elsevier. 2019. p. 135. ISBN 978-0-12-819400-3. https://books.google.com/books?id=4l6wDwAAQBAJ&pg=PA135. 
  13. ↑ "ACE2 protein expression summary". The Human Protein Atlas. https://www.proteinatlas.org/ENSG00000130234-ACE2. 
  14. ↑ 14.0 14.1 "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews. Molecular Cell Biology 23 (1): 3–20. January 2022. doi:10.1038/s41580-021-00418-x. PMID 34611326. 
  15. ↑ 15.0 15.1 15.2 15.3 "Chapter 25: ACE2 Cell Biology, Regulation, and Physiological Functions". The Protective Arm of the Renin Angiotensin System (RAS): Functional Aspects and Therapeutic Implications. The Protective Arm of the Renin Angiotensin System (Ras). Academic Press. 2015. pp. 185–189. doi:10.1016/B978-0-12-801364-9.00025-0. ISBN 978-0-12-801364-9. 
  16. ↑ "Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)". The Journal of Biological Chemistry 280 (34): 30113–30119. August 2005. doi:10.1074/jbc.M505111200. PMID 15983030. 
  17. ↑ "Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: a positive feedback mechanism in the RAS". Journal of Molecular and Cellular Cardiology 66: 167–176. January 2014. doi:10.1016/j.yjmcc.2013.11.017. PMID 24332999. 
  18. ↑ "Regulation of Angiotensin-Converting Enzyme 2: A Potential Target to Prevent COVID-19?". Frontiers in Endocrinology 12. 2021. doi:10.3389/fendo.2021.725967. PMID 34745001. 
  19. ↑ "Angiotensin-converting enzyme 2 as a potential therapeutic target for COVID-19: A review". Journal of Pharmaceutical Analysis 12 (2): 215–220. December 2021. doi:10.1016/j.jpha.2021.12.003. PMID 34934510. 
  20. ↑ "Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas". Proceedings of the National Academy of Sciences of the United States of America 100 (14): 8258–8263. July 2003. doi:10.1073/pnas.1432869100. PMID 12829792. Bibcode: 2003PNAS..100.8258S. 
  21. ↑ "A protein complex in the brush-border membrane explains a Hartnup disorder allele". FASEB Journal 22 (8): 2880–2887. August 2008. doi:10.1096/fj.08-107300. PMID 18424768. 
  22. ↑ "Molecular basis for the interaction of the mammalian amino acid transporters B0AT1 and B0AT3 with their ancillary protein collectrin". The Journal of Biological Chemistry 290 (40): 24308–24325. October 2015. doi:10.1074/jbc.M115.648519. PMID 26240152. 
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  33. ↑ 33.0 33.1 "ACE2/ADAM17/TMPRSS2 Interplay May Be the Main Risk Factor for COVID-19". Frontiers in Immunology 11. 2020. doi:10.3389/fimmu.2020.576745. PMID 33117379. 
  34. ↑ 34.0 34.1 34.2 "Structural insights into ACE2 interactions and immune activation of SARS-CoV-2 and its variants: an in-silico study". Journal of Biomolecular Structure & Dynamics 43 (2): 665–678. February 2025. doi:10.1080/07391102.2023.2283158. PMID 37982275. 
  35. ↑ "SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway". Cell Research 18 (2): 290–301. February 2008. doi:10.1038/cr.2008.15. PMID 18227861. Bibcode: 2008CelRe..18..290W. 
  36. ↑ "Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells". Virology 517: 3–8. April 2018. doi:10.1016/j.virol.2017.12.015. PMID 29275820. 
  37. ↑ "Getting in on the action: New tools to see SARS-CoV-2 infect a cell". Cell Chemical Biology 30 (3): 233–234. March 2023. doi:10.1016/j.chembiol.2023.02.010. PMID 36931249. 
  38. ↑ "SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2". Circulation Research 128 (9): 1323–1326. April 2021. doi:10.1161/CIRCRESAHA.121.318902. PMID 33784827. 
  39. ↑ "SARS-CoV-2-Induced Myocarditis: A State-of-the-Art Review". Viruses 15 (4): 916. April 2023. doi:10.3390/v15040916. PMID 37112896. 
  40. ↑ "SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS". European Journal of Clinical Investigation 39 (7): 618–625. July 2009. doi:10.1111/j.1365-2362.2009.02153.x. PMID 19453650. 
  41. ↑ "Myocarditis associated with Covid-19 disease: A systematic review of published case reports and case series". International Journal of Clinical Practice 75 (11). November 2021. doi:10.1111/ijcp.14470. PMID 34235815. 
  42. ↑ "COVID-19 and the Heart". Circulation Research 126 (10): 1443–1455. May 2020. doi:10.1161/CIRCRESAHA.120.317055. PMID 32252591. 
  43. ↑ "Understanding Glycans in COVID-19 Drug Design" (in en-US). Genetic Engineering and Biotechnology News. 1 April 2020. https://www.genengnews.com/insights/understanding-glycans-in-covid-19-drug-design/. 
  44. ↑ "The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice". Experimental Physiology 93 (5): 543–548. May 2008. doi:10.1113/expphysiol.2007.040048. PMID 18448662. 
  45. ↑ "Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease". Shock 46 (3): 239–248. September 2016. doi:10.1097/SHK.0000000000000633. PMID 27082314. "Once SARS-CoV binds to its receptor, the abundance on the cell surface, mRNA expression and the enzymatic activity of ACE2 are significantly reduced. ... These effects are, in part, due to enhanced shedding/internalizing processes. ... The spike protein binds to ACE2 and subsequently down regulated ACE2 protein expression and resulted in worsened acid aspiration pneumonia". 
  46. ↑ "Mechanisms of SARS-CoV-2 Transmission and Pathogenesis". Trends in Immunology 41 (12): 1100–1115. December 2020. doi:10.1016/j.it.2020.10.004. PMID 33132005. 
  47. ↑ "Good ACE, bad ACE do battle in lung injury, SARS". Nature Medicine 11 (8): 821–822. August 2005. doi:10.1038/nm0805-821. PMID 16079870. 
  48. ↑ "Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19". Journal of Travel Medicine 27 (3). May 2020. doi:10.1093/jtm/taaa041. PMID 32186711. 
  49. ↑ "Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis". BMJ 345 (jul11 1). July 2012. doi:10.1136/bmj.e4260. PMID 22786934. "Our results suggest an important role of ACE inhibitors, but not ARBs, in reducing the risk of pneumonia. These data may discourage the withdrawal of ACE inhibitors in some patients with tolerable adverse events (namely, cough) who are at particularly high risk of pneumonia. ACE inhibitors also lowered the risk of pneumonia related mortality, mainly in patients with established disease, but the robustness of the evidence was weaker.". 
  50. ↑ "Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19". Circulation Research 126 (12): 1671–1681. June 2020. doi:10.1161/CIRCRESAHA.120.317134. PMID 32302265. 
  51. ↑ "COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence?". JAMA 323 (18): 1769–1770. May 2020. doi:10.1001/jama.2020.4812. PMID 32208485. 
  52. ↑ "Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers". European Society of Cardiology (ESC). 13 March 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang. 
  53. ↑ "EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic". European Medicines Agency (EMA). 27 March 2020. https://www.ema.europa.eu/en/news/ema-advises-continued-use-medicines-hypertension-heart-kidney-disease-during-covid-19-pandemic. 
  54. ↑ "HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19". American College of Cardiology (ACC). 27 March 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19. 
  55. ↑ "Plasma ACE2 predicts outcome of COVID-19 in hospitalized patients". PLOS ONE 16 (6). 2021. doi:10.1371/journal.pone.0252799. PMID 34086837. Bibcode: 2021PLoSO..1652799K. 
  56. ↑ "Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2". Communications Biology 4 (1). April 2021. doi:10.1038/s42003-021-02030-3. PMID 33846513. 
  57. ↑ "Human variation in the protein receptor ACE2 affects its binding affinity to SARS-CoV-2 in a variant-dependent manner". Journal of Biomolecular Structure & Dynamics 41 (7): 2947–2955. February 2022. doi:10.1080/07391102.2022.2042387. PMID 35196964. 
  58. ↑ 58.0 58.1 "Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants". PLOS Computational Biology 18 (3). March 2022. doi:10.1371/journal.pcbi.1009922. PMID 35235558. Bibcode: 2022PLSCB..18E9922M. 
  59. ↑ 59.0 59.1 "Mutants of human ACE2 differentially promote SARS-CoV and SARS-CoV-2 spike mediated infection". PLOS Pathogens 17 (7). July 2021. doi:10.1371/journal.ppat.1009715. PMID 34270613. 
  60. ↑ "Polymorphisms and mutations of ACE2 and TMPRSS2 genes are associated with COVID-19: a systematic review". European Journal of Medical Research 27 (1). February 2022. doi:10.1186/s40001-022-00647-6. PMID 35193695. 
  61. ↑ "Angiotensin-converting enzyme 2-at the heart of the COVID-19 pandemic". Cell 186 (5): 906–922. March 2023. doi:10.1016/j.cell.2023.01.039. PMID 36787743. 
  62. ↑ "The human genetic epidemiology of COVID-19". Nature Reviews. Genetics 23 (9): 533–546. September 2022. doi:10.1038/s41576-022-00478-5. PMID 35501396. 
  63. ↑ 63.0 63.1 "Angiotensin-converting enzyme 2-at the heart of the COVID-19 pandemic". Cell 186 (5): 906–922. March 2023. doi:10.1016/j.cell.2023.01.039. PMID 36787743. 
  64. ↑ 64.0 64.1 64.2 64.3 "Engineered soluble ACE2 receptor: Responding to change with change". Frontiers in Immunology 13. 2022. doi:10.3389/fimmu.2022.1084331. PMID 36741399. 
  65. ↑ 65.0 65.1 65.2 "Interference With the Renin–Angiotensin System (RAS): Classical Inhibitors and Novel Approaches". Encyclopedia of Endocrine Diseases. Elsevier. 2019. pp. 523–530. doi:10.1016/b978-0-12-801238-3.65341-2. ISBN 978-0-12-812200-6. 
  66. ↑ "Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2". Cell 181 (4): 905–913.e7. May 2020. doi:10.1016/j.cell.2020.04.004. PMID 32333836. 
  67. ↑ 67.0 67.1 "Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2". Science 369 (6508): 1261–1265. September 2020. doi:10.1126/science.abc0870. PMID 32753553. Bibcode: 2020Sci...369.1261C. 
  68. ↑ "Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants". Nature Chemical Biology 18 (3): 342–351. March 2022. doi:10.1038/s41589-021-00965-6. PMID 35046611. 
  69. ↑ "A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome". Critical Care 21 (1). September 2017. doi:10.1186/s13054-017-1823-x. PMID 28877748. 
  70. ↑ "New Drugs and Therapies in Pulmonary Arterial Hypertension". International Journal of Molecular Sciences 24 (6): 5850. March 2023. doi:10.3390/ijms24065850. PMID 36982922. 
  71. ↑ "Apeiron Biologics moves forward with APN01 for treatment of COVID-19". www.thepharmaletter.com. https://www.thepharmaletter.com/article/apeiron-biologics-moves-forward-with-apn01-for-treatment-of-covid-19. 



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