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Biochem Biophys Rep . The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve

tetano

tetano

Editor, Senior Moderator
Biochem Biophys Rep


. 2021 Mar;25:100907.
doi: 10.1016/j.bbrep.2021.100907. Epub 2021 Jan 13.
The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus - evolved or yet to evolve


Anshul Budhraja[SUP] 1 2 3 [/SUP], Sakshi Pandey[SUP] 1 2 3 [/SUP], Srinivasaraghavan Kannan[SUP] 4 [/SUP], Chandra S Verma[SUP] 4 5 6 [/SUP], Prasanna Venkatraman[SUP] 2 3 [/SUP]



Affiliations
Free PMC article

Abstract

Recent research on the SARS-CoV-2 pandemic has exploded around the furin-cleavable polybasic insert PRRAR↓S, found within the spike protein. The insert and the receptor-binding domain, (RBD), are vital clues in the Sherlock Holmes-like investigation into the origin of the virus and in its zoonotic crossover. Based on comparative analysis of the whole genome and the sequence features of the insert and the RBD domain, the bat and the pangolin have been proposed as very likely intermediary hosts. In this study, using the various databases, in-house developed tools, sequence comparisons, structure-guided docking, and molecular dynamics simulations, we cautiously present a fresh, theoretical perspective on the SARS-CoV-2 virus activation and its intermediary host. They are a) the SARS-CoV-2 has not yet acquired a fully optimal furin binding site or this seemingly less optimal sequence, PRRARS, has been selected for survival; b) in structural models of furin complexed with peptides, PRRAR↓S binds less well and with distinct differences as compared to the all basic RRKRR↓S; c) these differences may be exploited for the design of virus-specific inhibitors; d) the novel polybasic insert of SARS-CoV-2 may be promiscuous enough to be cleaved by multiple enzymes of the human airway epithelium and tissues which may explain its unexpected broad tropism; e) the RBD domain of the feline coronavirus spike protein carries residues that are responsible for high-affinity binding of the SARS-CoV-2 to the ACE 2 receptor; f) en route zoonotic transfer, the virus may have passed through the domestic cat whose very human-like ACE2 receptor and furin may have played some role in optimizing the traits required for zoonotic transfer.

Keywords: Feline CoV; Furin; Host; Proteases; RBD; SARS-CoV-2; Spike protein.
 
QUOTE]A more alarming and dismal possibility is that the novel SARS-CoV-2 is en route to evolving into an even more virulent strain by acquiring a fully optimized furin site or sites for other enzymes. Or as reported with other viruses, such a fully optimized furin site may have attenuated infectivity and the strain with a less than optimal binding sequence but with a distinct survival advantage may have remained. Its lethality in certain geographical conditions may be due to the host factors such as the immune response and the proteolytic environment. It seems that a detailed characterization of the proteases that can cleave the spike protein and their efficiency correlated with protease expression/activity in patients is needed to clarify these possibilities. Undoubtedly these are not easy experiments to perform but to fully understand the evolution of the current SARS-Cov2 and any SARS of the future, such studies seem inevitable. In the absence of such experimental evidence, we acknowledge that our analysis remains predominantly speculative in nature.[/QUOTE]

and

In summary, our investigations suggest that either the SARS-CoV-2 is in transit on its evolutionary path to gain a fully optimized furin site or it may have promiscuously adapted to the host proteolytic environment for its own better survival. With the selection of residues with lowered binding potential at the P5 and P2 positions, the binding mode seems to have been carefully adapted, posing both a challenge and opportunity for inhibitor design. Our analysis also shows that the polybasic site and the RBD domain of SARS-CoV-2 spike protein, seem to have evolved along the lines of feline coronavirus spike protein providing substantial evidence for the domestic cat as a possible intermediary host during the zoonotic transfer of the SARS-CoV-2 .
Click to expand...
 
 
Whilst not in the right area, this article report (distressing) shows how easily disease might spread between cats, and as they were destined for restaurants, how easy it would be for a jump to humans. It is conceivable that an imported (and infected) pangolin dies at a wet market, gets eaten / fed to cats, and completes viral evolution ready for a jump to humans. However, we know that the outbreak predates the Wuhan wet market, but this could be part of the puzzle perhaps?

https://www.dailymail.co.uk/news/art...iny-boxes.html
 
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