Discovery of Potent Pyrazoline‐Based Covalent SARS‐CoV‐2 Main Protease Inhibitors**
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Abstract
While vaccines and antivirals are now being deployed for the current SARS‐CoV‐2 pandemic, we require additional antiviral therapeutics to not only effectively combat SARS‐CoV‐2 and its variants, but also future coronaviruses. All coronaviruses have relatively similar genomes that provide a potential exploitable opening to develop antiviral therapies that will be effective against all coronaviruses. Among the various genes and proteins encoded by all coronaviruses, one particularly “druggable” or relatively easy‐to‐drug target is the coronavirus Main Protease (3CL pro or Mpro), an enzyme that is involved in cleaving a long peptide translated by the viral genome into its individual protein components that are then assembled into the virus to enable viral replication in the cell. Inhibiting Mpro with a small‐molecule antiviral would effectively stop the ability of the virus to replicate, providing therapeutic benefit. In this study, we have utilized activity‐based protein profiling (ABPP)‐based chemoproteomic approaches to discover and further optimize cysteine‐reactive pyrazoline‐based covalent inhibitors for the SARS‐CoV‐2 Mpro. Structure‐guided medicinal chemistry and modular synthesis of di‐ and tri‐substituted pyrazolines bearing either chloroacetamide or vinyl sulfonamide cysteine‐reactive warheads enabled the expedient exploration of structure‐activity relationships (SAR), yielding nanomolar potency inhibitors against Mpro from not only SARS‐CoV‐2, but across many other coronaviruses. Our studies highlight promising chemical scaffolds that may contribute to future pan‐coronavirus inhibitors.
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SciScore for 10.1101/2022.03.05.483025: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: …
SciScore for 10.1101/2022.03.05.483025: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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