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Recombinant human ACE2: potential therapeutics of SARS-CoV-2 infection and its complication

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Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pneumonia outbreak in Wuhan city, China, followed by global spread [1, 2]. As of 9 April, 2020, millions of confirmed cases of SARS-CoV-2 infection have been reported, and the global death toll of SARS-CoV-2 infection has surged to tens of thousands of victims, making it a public health emergency of international concern (PHEIC). However, no specific antiviral drug or vaccine for SARS-CoV-2 treatment exists. The high infectivity and the increasing fatality of SARS-CoV-2 highlight the demand for drug discovery. SARS-CoV-2 is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) [2]. Full-genome sequencing analysis indicated that SARS-CoV-2 shares a high-sequence identity with SARS-CoV [3]. The spike protein (S-protein) of coronaviruses interacts with cell receptors to mediate viral entry into target cells [4]. Additional evidence suggests that both SARS-CoV and SARS-CoV-2 employ angiotensin-converting enzyme 2 (ACE2) as the entry receptor and that the receptor-binding domain (RBD) of the S-protein directly binds to ACE2, triggering endocytosis of virus particles [5,6,7]. A recent study suggested that the binding affinity between ACE2 and the RBD of SARS-CoV-2 is 10–20 times stronger than that with the RBD of SARS-CoV [5], which likely explains the increased infectivity of SARS-CoV-2.

ACE2 is not only a functional receptor of coronaviruses, but also acts as an important negative regulator of the renin–angiotensin system (RAS) through conversion of the vasoconstrictor angiotensin II (Ang II) to its metabolite angiotensin-(1–7) (Ang 1–7) and angiotensin I(Ang I) to angiotensin-(1–9) (Ang 1–9) [7,8,9]. The ACE2/Ang 1–7 axis plays a series of roles in the improvement of endothelial dysfunction, anti-inflammation, anti-hypertension, anti-thrombus, and anti-fibrosis activity, and cardiovascular protection [10,11,12,13,14]. The protective effect of ACE2 is associated with attenuating Ang II levels and increasing Ang 1–7 levels in lung pathophysiology [10]. Emerging evidence has shown that RAS signaling and ACE2 play crucial roles in SARS-CoV-induced acute respiratory distress syndrome (ARDS) and lethal avian influenza A(H5N1, H7N9)-induced acute lung injury (ALI) [14, 15]. According to pathological findings, SARS-CoV-2 is also associated with lung failure and ARDS [16], and the majority of severely ill patients with SARS-CoV-2 infection have underlying comorbidities, such as cardiovascular disease, diabetes, and cerebrovascular disease [1]. The anti-trypanosomal agent diminazene aceturate (DIZE) was reported to be an ACE2 activator, which has a structure similar to that of the established ACE2 activator xanthenone [17, 18]. DIZE was suggested to exert protective effects in cardiovascular disease through modulating ACE2 activation and expression to increase Ang 1–7 production and improve vascular function [17]. Owing to the role of ACE2 in the entry of SARS-CoV-2, the upregulated expression of ACE2 had an unwanted effect. Therefore, DIZE is not suggested to be applied in the treatment of SARS-CoV-2 infection. However, the addition of exogenous ACE2 could be a potential treatment for SARS-CoV-2 infection, which might not only restrain the spread of SARS-CoV-2 by blocking its interaction with ACE2 on the host cell, but also modulate RAS to treat SARS-CoV-2-related underlying comorbidities and protect the lung from developing ARDS.

Given that ACE2 is generated mainly in Clara cells and type II alveolar epithelial cells, the production of ACE2 is severely impaired after epithelial injury in the development of ARDS [19]. In addition, the expression of ACE2 is also severely decreased in patients with pulmonary fibrosis [20]. Therefore, injection of recombinant human ACE2 (rhACE2) is currently considered for treating ARDS and pulmonary arterial hypertension [21]. Circulatory levels of ACE2 activity were markedly increased by rhACE2, which further effectively lowered Ang II levels and generated Ang 1–7 from Ang II (Fig. 1). Although Ang II receptor and ACE blockage were also effective in lung failure in animal models, this treatment could cause potential adverse effects, causing systemic hypotension in humans [22]. As shown in Fig. 1, rhACE2 also acts as a potential therapy for hypertension, heart failure, kidney injury, and liver fibrosis [22,23,24].

Fig. 1: The mechanism and functions of rhACE2.
figure1

rhACE2 is able to lower Ang II levels and increase Ang 1–7 levels effectively and exert protective effects in the heart, lung, liver, and kidney.

Currently, phase I (NCT00886353) and phase II (NCT01597635) clinical studies with a recombinant version of the catalytic ectodomain of human ACE2 (GSK2586881) have been successfully completed, providing safety and efficacy for ARDS treatment [25, 26]. The administration of rhACE2 was well tolerated without clinically significant hemodynamic changes in healthy subjects and patients with ARDS [26]. During the administration period, no antibodies to rhACE2 were detected, and no serious adverse events were reported [25]. The twice-daily doses of GSK2586881 treatment-regulated angiotensin system peptide, leading to a significant reduction in the concentration of Ang II, accompanied by a rapid rise in Ang 1–7 and Ang 1–5 concentrations, and caused a reduction in IL-6 concentration [26]. However, given the small cohort of critically ill patients, infusion of GSK2586881 did not contribute to ameliorated ARDS through physiological or clinical measures, and a clear role of GSK2586881 in the increased reports of adverse events referring to hypernatremia, pneumonia, dysphagia, and rash was difficult to establish. Therefore, to assess clinical outcomes powerfully, further clinical trials need a larger sample size. Recently, Monteil et al. [27] reported that hrACE2 could significantly inhibit SARS-CoV-2 infection of Vero-E6 cells, and of human capillary and kidney organoids, providing an evidence that rhACE2 might not only reduce lung injury but also block early entry of SARS-CoV-2 infections in target cells. Further studies are needed to illuminate the effect of hrACE2 in SARS-CoV-2 infections from bench to clinic. To ensure the quality of the data and clinical success of rhACE2, the trials for using rhACE2 in patients with SARS-CoV-2 infection or ARDS should consider the patient’s stratification and continuous infusion dose. First, various plasma Ang II levels may pose some difficulties in identifying responders. Hence, before GSK2586881 infusion, the Ang II concentrations and the ratio of ACE2/ACE activity of enrolled patients were evaluated for improved risk stratification. ACE gene insertion/deletion (I/D) polymorphisms play an important role in the development of hypertension, nephritis, and cardiovascular diseases in different ethnic populations by influencing ACE and Ang II activities [28, 29]. Identifying the specific population that is most likely to benefit from rhACE2 represents a bright prospect. Second, due to the short half-life of soluble ACE2 in vivo, a continuous infusion of rhACE2 may enhance efficacy. In addition, an excess of rhACE2 is likely to influence the balance of the RAS; therefore, it is important to identify the effective infusion dose to prevent underlying RAS-related adverse events. Recently, it was reported that a chimeric fusion of rhACE2 and IgG2 Fc fragments could improve rhACE2 plasma stability [22]. This rhACE2-Fc fusion protein retained full peptidase activity and had extended plasma half-life in mice [24]. The strategy for rhACE2-Fc will be expected to provide patients with added convenience, largely reducing administration frequency and greatly improving treatment effectiveness [30]. Taken together, these findings indicate that rhACE2 would represent a potential therapeutic strategy for SARS-CoV-2 infection and its complications.

References

  1. 1.

    Zhu N, Zhang DY, Wang WL, Li XW, Yang B, Song JD, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382:727–33.

    Article  CAS  Google Scholar 

  2. 2.

    Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5:536–44.

    Article  CAS  Google Scholar 

  3. 3.

    Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–3.

    Article  CAS  Google Scholar 

  4. 4.

    Han DP, Penn-Nicholson A, Cho MW. Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology. 2006;350:15–25.

    Article  CAS  Google Scholar 

  5. 5.

    Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367:1260–3.

    Article  CAS  Google Scholar 

  6. 6.

    Yan RH, Zhang YY, Li YN, Xia L, Zhou Q. Structure of dimeric full-length human ACE2 in complex with B0AT1. bioRxiv. 2020. https://doi.org/10.1101/2020.02.17.951848.

  7. 7.

    Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically-proven protease inhibitor. Cell. 2020. https://doi.org/10.1016/j.cell.2020.02.052.

  8. 8.

    Acharya KR, Sturrock ED, Riordan JF, Ehlers MR. Ace revisited: a new target for structure-based drug design. Nat Rev Drug Disco. 2003;2:891–902.

    Article  CAS  Google Scholar 

  9. 9.

    Unger T, Chung O, Csikos T, Culman J, Gallinat S, Gohlke P, et al. Angiotensin receptors. J Hypertens Suppl. 1996;14:S95–103.

    Article  CAS  Google Scholar 

  10. 10.

    Shenoy V, Qi Y, Katovich MJ, Raizada MK. ACE2, a promising therapeutic target for pulmonary hypertension. Curr Opin Pharmacol. 2011;11:150–5.

    Article  CAS  Google Scholar 

  11. 11.

    Zhu YZ, Zhu YC, Li J, Schäfer H, Schmidt W, Yao T, et al. Effects of losartan on haemodynamic parameters and angiotensin receptor mRNA levels in rat heart after myocardial infarction. J Renin Angiotensin Aldosterone Syst. 2000;1:257–62.

    Article  CAS  Google Scholar 

  12. 12.

    Zhu YZ, Zhu YC, Wang ZJ, Lu Q, Lee HS, Unger T. Time-dependent apoptotic development and pro-apoptotic genes expression in rat heart after myocardial infarction. Jpn J Pharmacol. 2001;86:355–8.

    Article  CAS  Google Scholar 

  13. 13.

    Turner AJ, Hooper NM. The angiotensin-converting enzyme gene family: genomics and pharmacology. Trends Pharmacol Sci. 2002;23:177–83.

    Article  CAS  Google Scholar 

  14. 14.

    Zou Z, Yan Y, Shu Y, Gao R, Sun Y, Li X, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014;5:3594. https://doi.org/10.1038/ncomms4594.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Yang P, Gu H, Zhao Z, Wang W, Cao B, Lai C, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014;4:7027. https://doi.org/10.1038/srep07027.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Xu Z, Shi L, Wang YJ, Zhang JY, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8:420–2.

    Article  CAS  Google Scholar 

  17. 17.

    Qaradakhi T, Gadanec LK, McSweeney KR, Tacey A, Apostolopoulos V, Levinger I, et al. The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases. Clin Exp Pharmacol Physiol. 2020;47:751–8.

    Article  CAS  Google Scholar 

  18. 18.

    Hernández Prada JA, Ferreira AJ, Katovich MJ, Shenoy V, Qi Y, Santos RA, et al. Structure-based identification of small-molecule angiotensin-converting enzyme 2 activators as novel antihypertensive agents. Hypertension. 2008;51:1312–7.

    Article  CAS  Google Scholar 

  19. 19.

    Wiener RS, Cao YX, Hinds A, Ramirez MI, Williams MC. Angiotensin converting enzyme 2 is primarily epithelial and is developmentally regulated in the mouse lung. J Cell Biochem. 2007;101:1278–91.

    Article  CAS  Google Scholar 

  20. 20.

    Li X, Molina-Molina M, Abdul-Hafez A, Uhal V, Xaubet A, Uhal BD. Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol. 2008;295:L178–85.

    Article  CAS  Google Scholar 

  21. 21.

    Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit Care. 2017;21:305. https://doi.org/10.1186/s13054-017-1882-z.

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Patel VB, Lezutekong JN, Chen X, Oudit GY. Recombinant human ACE2 and the angiotensin 1-7 axis as potential new therapies for heart failure. Can J Cardiol. 2017;33:943–6.

    Article  Google Scholar 

  23. 23.

    Mak KY, Chin R, Cunningham SC, Habib MR, Torresi J, Sharland AF, et al. ACE2 therapy using adeno-associated viral vector inhibits liver fibrosis in mice. Mol Ther. 2015;23:1434–43.

    Article  CAS  Google Scholar 

  24. 24.

    Liu P, Wysocki J, Souma T, Ye M, Ramirez V, Zhou B, et al. Novel ACE2-Fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation. Kidney Int. 2018;94:114–25.

    Article  CAS  Google Scholar 

  25. 25.

    Haschke M, Schuster M, Poglitsch M, Loibner H, Salzberg M, Bruggisser M, et al. Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. Clin Pharmacokinet. 2013;52:783–92.

    Article  CAS  Google Scholar 

  26. 26.

    Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21:234. https://doi.org/10.1186/s13054-017-1823-x.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020. https://doi.org/10.1016/j.cell.2020.04.004.

  28. 28.

    Sayed-Tabatabaei FA, Oostra BA, Isaacs A, van Duijn CM, Witteman JC. ACE polymorphisms. Circ Res. 2006;98:1123–33.

    Article  CAS  Google Scholar 

  29. 29.

    Mu G, Xiang Q, Zhou S, Xie Q, Liu Z, Zhang Z, et al. Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis. Pharmacogenomics. 2019;20:189–212.

    Article  CAS  Google Scholar 

  30. 30.

    Kruse RL. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000Res. 2020;9:72. https://doi.org/10.12688/f1000research.22211.2.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation (No. 81973320, No.81673509, and No. 81903714) of China and the Macau Science and Technology Development Fund (FDCT) (No.0002/2019/APD, 067/2018/A2, 033/2017/AMJ, and 0007/2019/AKP).

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Correspondence to Yimin Cui or Yizhun Zhu.

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Pang, X., Cui, Y. & Zhu, Y. Recombinant human ACE2: potential therapeutics of SARS-CoV-2 infection and its complication. Acta Pharmacol Sin 41, 1255–1257 (2020). https://doi.org/10.1038/s41401-020-0430-6

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