ACE2Fc: A Promising Therapy for SARS-Cov2 Infection
Main Article Content
Abstract
SARS-CoV2 entry is mediated by binding of viral spike-protein (S) to the transmembrane Angiotensin-Converting Enzyme-2 (ACE2) of the host cell. Thus, to prevent transmission of disease, strategies to abrogate the interaction are important. However, ACE2 cannot be blocked since its normal function is to convert the Angiotensin II peptide to Angiotensin(1-7) to reduce hypertension. This work reports a recombinant cell line secreting soluble ACE2-ectopic domain (MFcS2), modified to increase binding and production efficacy and fused to human immunoglobulin-Fc. While maintaining its enzymatic activity, the molecule trapped and neutralized SARS-CoV2 virus in vitro with an IC50 of 64 nM. In vivo, with no pathology in the vital organs, it inhibited the viral load in lungs in SARS-CoV2 infected Golden-Syrian-hamster. The Intravenous pharmacokinetic profiling of MFcS2 in hamster at a dose of 5 mg/Kg presented a maximum serum concentration of 23.45 µg/mL with a half-life of 29.56 hrs. These results suggest that MFcS2 could be used as an effective decoy based therapeutic strategy to treat COVID19. This work also reports usage of a novel oral-cancer cell line as in vitro model of SARS-Cov2 infection, validated by over expressing viral-defence pathways upon RNA-seq analysis and over-expression of ACE2 and TMPRSS2 upon growth in hyperglycaemic condition.
Article Details
How to Cite
SMITHA, P.K. et al.
ACE2Fc: A Promising Therapy for SARS-Cov2 Infection.
Medical Research Archives, [S.l.], v. 10, n. 12, dec. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3322>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v10i12.3322.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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8. Pan H, Peto R, Henao-Restrepo A-M, et al. Repurposed Antiviral Drugs for Covid-19-Interim WHO Solidarity Trial Results. Lancet. 2022;399:1941-1953.
9. Hoffmann M, Mösbauer K, Hofmann-Winkler H, et al. Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2. Nature. 2020;585(7826):588-590.
10. Maisonnasse P, Guedj J, Contreras V, et al. Hydroxychloroquine use against SARS-CoV-2 infection in non-human primates. Nature. 2020;585(7826):584-587.
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12. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for oral treatment of Covid-19 in nonhospitalized patients. N Engl J Med. 2022;386(6):509-520.
13. Cully M. A tale of two antiviral targets - and the COVID-19 drugs that bind them. Nat Rev Drug Discov. 2022;21(1):3-5. doi:10.1038/D41573-021-00202-8
14. Rubin R. Baricitinib Is First Approved COVID-19 Immunomodulatory Treatment. JAMA. 2022;327(23):2281.
15. Zhang Z, Zeng E, Zhang L, et al. Potent prophylactic and therapeutic efficacy of recombinant human ACE2-Fc against SARS-CoV-2 infection in vivo. Cell Discov. 2021;7(1). doi:10.1038/s41421-021-00302-0
16. Liu P, Xie X, Gao L, Jin J. Designed variants of ACE2-Fc that decouple anti-SARS-CoV-2 activities from unwanted cardiovascular effects. Int J Biol Macromol. 2020;165:1626-1633.
17. Higuchi Y, Suzuki T, Arimori T, et al. Engineered ACE2 receptor therapy overcomes mutational escape of SARS-CoV-2. Nat Commun. 2021;12(1):3802. doi:10.1038/s41467-021-24013-y
18. Siriwattananon K, Manopwisedjaroen S, Kanjanasirirat P, et al. Development of Plant-Produced Recombinant ACE2-Fc Fusion Protein as a Potential Therapeutic Agent Against SARS-CoV-2. Front Plant Sci. 2021;11(January):1-12. doi:10.3389/fpls.2020.604663
19. Ferrari M, Mekkaoui L, Ilca FT, et al. Characterization of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV-2 variants. J Virol. 2021;95(19):e00685-21.
20. Castilho A, Schwestka J, Kienzl NF, et al. Generation of enzymatically competent SARS-CoV-2 decoy receptor ACE2-Fc in glycoengineered Nicotiana benthamiana. Biotechnol J. 2021;16(6):1-6. doi:10.1002/biot.202000566
21. Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-273.
22. Samavati L, Uhal BD. ACE2, Much More Than Just a Receptor for SARS-COV-2 . Front Cell Infect Microbiol . 2020;10:317. https://www.frontiersin.org/article/10.3389/fcimb.2020.00317.
23. Shang J, Ye G, Shi K, et al. Structural basis of receptor recognition by SARS-CoV-2. Nature. 2020;581(7807):221-224. doi:10.1038/s41586-020-2179-y
24. Monteil V, Kwon H, Prado P, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020;181(4):905-913.
25. Zoufaly A, Poglitsch M, Aberle JH, et al. Human recombinant soluble ACE2 in severe COVID-19. Lancet Respir Med. 2020;8(11):1154-1158. doi:10.1016/S2213-2600(20)30418-5
26. Liu P, Wysocki J, Souma T, 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(1):114-125.
27. Glasgow A, Glasgow J, Limonta D, et al. Engineered ACE2 receptor traps potently neutralize SARS-CoV-2. Proc Natl Acad Sci. 2020;117(45):28046-28055.
28. Linsky TW, Vergara R, Codina N, et al. De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2. Science (80- ). 2020;370(6521):1208-1214.
29. Chan KK, Dorosky D, Sharma P, et al. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science (80- ). 2020;369(6508):1261-1265. doi:10.1126/SCIENCE.ABC0870
30. Miller A, Leach A, Thomas J, et al. A super-potent tetramerized ACE2 protein displays enhanced neutralization of SARS-CoV-2 virus infection. Sci Rep. 2021;11(1):1-13.
31. Cameroni E, Bowen JE, Rosen LE, et al. Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Nature. 2022;602(7898):664-670.
32. Ikemura N, Taminishi S, Inaba T, et al. An engineered ACE2 decoy neutralizes the SARS-CoV-2 Omicron variant and confers protection against infection in vivo. Sci Transl Med. 2022;14(650). doi:10.1126/SCITRANSLMED.ABN7737
33. Dwivedi N, Gangadharan C, Pillai V, Kuriakose MA, Suresh A, Das M. Establishment and characterization of novel autologous pair cell lines from two Indian non‑habitual tongue carcinoma patients. Oncol Rep. 2022;48(3):1-12. doi:10.3892/OR.2022.8362/HTML
34. Andrade MA, Chacon P, Merelo JJ, Morán F. Evaluation of secondary structure of proteins from UV circular dichroism spectra using an unsupervised learning neural network. Protein Eng Des Sel. 1993;6(4):383-390.
35. Chen S, Zhou Y, Chen Y, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018;34(17):i884-i890.
36. Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15-21.
37. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):1-21.
38. Wu T, Hu E, Xu S, et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innov. 2021;2(3):100141.
39. Zhang Y, Huo M, Zhou J, Xie S. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed. 2010;99(3):306-314.
40. Cieza RJ, Golob JL, Colacino JA, Wobus CE. Comparative analysis of public RNA-sequencing data from human intestinal enteroid (HIEs) infected with enteric RNA viruses identifies universal and virus-specific epithelial responses. Viruses. 2021;13(6):1059.
41. Liao Y-H, Zheng J-Q, Zheng C-M, Lu K-C, Chao Y-C. Novel molecular evidence related to COVID-19 in patients with diabetes mellitus. J Clin Med. 2020;9(12):3962.
42. Herman-Edelstein M, Guetta T, Barnea A, et al. Expression of the SARS-CoV-2 receptorACE2 in human heart is associated with uncontrolled diabetes, obesity, and activation of the renin angiotensin system. Cardiovasc Diabetol. 2021;20(1):1-14.
43. D’Onofrio N, Scisciola L, Sardu C, et al. Glycated ACE2 receptor in diabetes: open door for SARS-COV-2 entry in cardiomyocyte. Cardiovasc Diabetol. 2021;20(1):1-16.
44. Okui T, Matsuda Y, Karino M, Hideshima K, Kanno T. Oral Mucosa Could Be an Infectious Target of SARS-CoV-2. Healthc (Basel, Switzerland). 2021;9(8). doi:10.3390/HEALTHCARE9081068
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