S1 Subunit and Host Proteases as Potential Therapeutic Avenues for the Treatment of COVID-19

Azher Arafah

Shafat Ali

Ali Yatoo

Md Ali

Muneeb Rehman

Abstract

The novel corona virus (SARS-CoV-2) that causes severe acute respiratory syndrome, now called COVID-19 initially originated in Wuhan city of China and later spread across borders and infected more than five million people and killed over 3.4 lakh people all over the globe. This disease has been announced as pandemic by WHO. So far, there has been not much progress in terms of drug development for fighting against this deadliest virus, also no existing drugs has been reported completely effective for COVID-19 treatment owing to lack of effective therapeutic targets and a broad understanding of the viral behavior in target cell. Some reports have found and confirmed that SARS-CoV-2 like others SARS-CoVs utilizes angiotensin converting enzyme-2 receptor for making entry into target cell by binding to the receptor with its S1 subunit and employing host cell proteases for cleaving S2 subunit at S2’ in order to fuse with cell membrane. Thus, simultaneous blocking of S1 subunit and inactivation of proteases seem to be promising therapeutic targets for the development of effective novel drugs. In current write up we hypothesize that S1 subunit and host proteases as potential therapeutic avenues for the treatment of COVID-19.

Key Words: S1 subunit, SARS-CoV-2, Spike (S) transmembrane glycoprotein, COVID-19

Background

Entry of corona viruses (CoVs) into target host cells occurs with the help of spike (S) transmembrane glycoprotein which projects out from the surface of virus in the form of homo-trimers (¹). This protein (S) consists of a small intracellular tail, a trans-membrane anchor, and a large sized ectodomain composed of receptor-binding S1 subunit, and cell membrane-fusing S2 subunit (²). S1 subunit initiates the process of viral entry via attaching with cell receptor while S2 subunit facilities the viral fusion with cell membrane (³). The protein S is cleaved at S2’ by proteases present in host cell (⁴) leading to the activation of this protein for fusion with cell membrane through a spectrum of permanent conformational modifications (⁵6). Thus, viral entry is a complicated process depending on combined event of protein S- receptor binding and proteolytic protein S processing (³).

Hypothesis

Though protein S of SARS-CoV-2 shows merely 75% similarity with the S protein of SARS-CoV as depicted from sequence analysis (⁷8) but S protein receptor-binding motif (RBM) analysis shows that majority of amino acid residues vital for receptor binding are conserved between SARS-CoV and, SARS-CoV-2, signifying that these two strains of CoVs make use of the same receptor for entering into host cell (⁹) which is Angiotensin converting enzyme 2 (ACE2) (⁸1011). Since the spike (S) protein is the viral component that with the cleaving action of host proteases facilitates the CoV-2 entry into the host cellular cytoplasm, thus a hypothesis is arises “could the blocking of viral S1 subunit and inhibiting of proteases simultaneously with host-friendly inhibitors make the CoV-2 handicapped and prevent its complete entry into target cells”. Figure 1 shows the mechanism of CoV-2 entry into target cell. The theoretical model for inhibiting receptor-binding S1and S′-proteases interplay is depicted in Figure 2 . We suggest that S1 subunit and host proteases as potential therapeutic avenues for the treatment of COVID-19.

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Figure 1

Mechanism of SARS-CoV-2 entry into target cell.

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Figure 2

Blocking of S1 Subunit and protease inhibition prevents the SARS-CoV-2 entry into target cell.

^{Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia}

^{Cytogenetics and Molecular Biology Laboratory, Centre of Research for Development, University of Kashmir, Hazratbal, Srinagar, Jammu and Kashmir, India}

^{Department of Biochemistry, Government Medical College (GMC-Srinagar), Karan Nagar, Srinagar, Jammu and Kashmir, India}

Muneeb U. Rehman: moc.liamg@hjbeenum

^{Address reprint requests to: Muneeb U. Rehman, Department of Clinical Pharmacy, College of Pharmacy, King Saud University, P.O. Box-2457, Riyadh 11451, Saudi Arabia; Phone/FAX: 0114670765}moc.liamg@hjbeenum

Received 2020 May 12; Accepted 2020 May 18.

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Notes

(ARCMED_2020_692)

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References

1. Tortorici M.A., Veesler DStructural insights into coronavirus entry. Adv Virus Res. 2019;105:93–116.[Google Scholar]
2. Li FStructure, function, and evolution of coronavirus spike proteins. Ann Rev Virol. 2016;3:237–261.[Google Scholar]
3. Walls A.C., Park Y.J., Tortorici M.AStructure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020;180:281–292.[PubMed][Google Scholar]
4. Millet J.K., Whittaker G.RHost cell proteases: critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015;202:120–134.[Google Scholar]
5. Park J.E., Li K., Barlan AProteolytic processing of Middle East respiratory syndrome coronavirus spikes expands virus tropism. Proc Natl Acad Sci U S A. 2016;113:12262–12267.[Google Scholar]
6. Walls A.C., Tortorici M.A., Snijder JTectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion. Proc Natl Acad Sci U S A. 2017;114:11157–11162.[Google Scholar]
7. Lu R., Zhao X., Li JGenomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395:565–574.[Google Scholar]
8. Zhou P., Yang X.L., Wang X.GA pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273.[Google Scholar]
9. Wan Y., Shang J., Graham RReceptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7):e00127.[Google Scholar]
10. Li W., Moore M.J., Vasilieva NAngiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450–454.[Google Scholar]
11. Kuba K., Imai Y., Rao SA crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med. 2005;11:875–879.[Google Scholar]