Abstract

Processing of certain viral proteins and bacterial toxins by host serine proteases is a frequent and critical step in virulence. The coronavirus spike glycoprotein contains three (S1, S2, and S2′) cleavage sites that are processed by human host proteases. The exact nature of these cleavage sites, and their respective processing proteases, can determine whether the virus can cross species and the level of pathogenicity. Recent comparisons of the genomes of the highly pathogenic SARS-CoV2 and MERS-CoV, with less pathogenic strains (e.g., Bat-RaTG13, the bat homologue of SARS-CoV2) identified possible mutations in the receptor binding domain and in the S1 and S2′ cleavage sites of their spike glycoprotein. However, there remains some confusion on the relative roles of the possible serine proteases involved for priming. Using anthrax toxin as a model system, we show that in vivo inhibition of priming by pan-active serine protease inhibitors can be effective at suppressing toxicity. Hence, our studies should encourage further efforts in developing either pan-serine protease inhibitors or inhibitor cocktails to target SARS-CoV2 and potentially ward off future pandemics that could develop because of additional mutations in the S-protein priming sequence in coronaviruses.

Highlights

  • The outer surface of coronaviruses contains a critical transmembrane spike glycoprotein that is essential for entry of viral particles into host cells

  • Furin and related PCs (PC2, PC1/3, PC4, PACE4, PC5/6, and PC7) are specialized serine with either a single dose 3mg/kg (I.P.) of compound 1, or two doses spaced by 2 h, or with vehicle endoproteases that cleave the multibasic motifs R-X-(R/K/X)-R↓(S)(V/A/L) [9,10,11]

  • All mice in the untreated group perished in roughly 33 h, in agreement with the published studies with this model, while a remarkable and significant increase in both median survival time (MST) and time to death (TTD) was observed in both groups treated with compound 1 (Figure 3B)

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Summary

Introduction

The outer surface of coronaviruses contains a critical transmembrane spike glycoprotein that is essential for entry of viral particles into host cells. This viral glycoprotein possesses a trimeric structure, which gives the virus its typical crown-like halo (Figure 1A). This outer protein contains domains and structural motifs that are essential for binding to host cells and for viral fusion. There are three proteolytic cleavage sites (S1, S2, and S20 ; Figure 1B) in the spike glycoprotein The sequence of these sites can determine whether the virus can cross species, for example from bats or camels to humans [5,6,7,8]. The cleavage site (S2) of sequence ATY↓MS (the arrow indicates the cleavage site) is likely cleaved by cathepsin

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