Insights into the Dynamics and Binding of Two Polyprotein Substrate Cleavage Points in the Context of the SARS-CoV-2 Main and Papain-like Proteases

Sanusi, Zainab K; Lobb, Kevin A

Title: Insights into the Dynamics and Binding of Two Polyprotein Substrate Cleavage Points in the Context of the SARS-CoV-2 Main and Papain-like Proteases
Creator: Sanusi, Zainab K
Creator: Lobb, Kevin A
Subject: To be catalogued
Date Issued: 2022
Date: 2022
Type: text
Type: article
Identifier: http://hdl.handle.net/10962/452773
Identifier: vital:75169
Identifier: xlink:href="https://doi.org/10.3390/molecules27238251"
Description: It is well known that vital enzymes in the replication process of the coronavirus are the SARS-CoV-2 PLpro and SARS-CoV-2 3CLpro, both of which are important targets in the search for anti-coronavirus agents. These two enzymes are responsible for cleavage at various polyprotein sites in the SARS-CoV-2 lifecycle. Herein, the dynamics of the polyprotein cleavage sequences for the boundary between non-structural proteins Nsp1 and Nsp2 (CS1) and between Nsp2 and Nsp3 (CS2) in complex with both the papain-like protein PLpro and the main protease 3CLpro were explored using computational methods. The post dynamics analysis reveals that CS1 and CS2 both have greater stability when complexed with PLpro. Of these two, greater stability is observed for the CS1–PLpro complex, while destabilization resulting in loss of CS2 from the PLpro active site is observed for CS2-PLpro, suggesting the rate of exchange by the papain-like protease is faster for CS2 compared to CS1. On the other hand, the 3CLpro main protease also reveals stability for CS1 suggesting that the main protease could also play a potential role in the cleavage at point CS1. However, destabilization occurs early in the simulation for the complex CLpro–CS2 suggesting a poor interaction and non-plausible protease cleavage of the polyprotein at CS2 by the main protease. These findings could be used as a guide in the development and design of potent COVID-19 antiviral inhibitors that mimic the CS1 cleavage site.
Format: computer
Format: online resource
Format: application/pdf
Format: 1 online resource (16 pages)
Format: pdf
Publisher: MDPI
Language: English
Relation: Molecules
Relation: Sanusi, Z.K. and Lobb, K.A., 2022. Insights into the Dynamics and Binding of Two Polyprotein Substrate Cleavage Points in the Context of the SARS-CoV-2 Main and Papain-like Proteases. Molecules, 27(23), p.8251
Relation: Molecules volume 27 number 23 p. 8251 2022 1420-3049
Rights: Publisher
Rights: Use of this resource is governed by the terms and conditions of the MDPI Open Access Statement (https://www.int-res.com/journals/terms-of-use/)
Rights: Open Access

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RU Research Unit in Bioinformatics (RUBi)

Lobb, Kevin Allan (Assoc Prof)

RU Department of Chemistry

SDG 03. Good Health and Well-Being

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