PreprintReviewVersion 1Preserved in Portico This version is not peer-reviewed
3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials
Version 1
: Received: 2 May 2024 / Approved: 6 May 2024 / Online: 7 May 2024 (16:44:24 CEST)
How to cite:
Amorim, V. M. D. F.; Soares, E. P.; Ferrari, A. S. D. A.; Merighi, D. G. S.; de Souza, R. F.; Guzzo, C. R.; Souza, A. S. D. 3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials. Preprints2024, 2024050326. https://doi.org/10.20944/preprints202405.0326.v1
Amorim, V. M. D. F.; Soares, E. P.; Ferrari, A. S. D. A.; Merighi, D. G. S.; de Souza, R. F.; Guzzo, C. R.; Souza, A. S. D. 3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials. Preprints 2024, 2024050326. https://doi.org/10.20944/preprints202405.0326.v1
Amorim, V. M. D. F.; Soares, E. P.; Ferrari, A. S. D. A.; Merighi, D. G. S.; de Souza, R. F.; Guzzo, C. R.; Souza, A. S. D. 3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials. Preprints2024, 2024050326. https://doi.org/10.20944/preprints202405.0326.v1
APA Style
Amorim, V. M. D. F., Soares, E. P., Ferrari, A. S. D. A., Merighi, D. G. S., de Souza, R. F., Guzzo, C. R., & Souza, A. S. D. (2024). 3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials. Preprints. https://doi.org/10.20944/preprints202405.0326.v1
Chicago/Turabian Style
Amorim, V. M. D. F., Cristiane Rodrigues Guzzo and Anacleto Silva de Souza. 2024 "3-Chymotrypsin-like Protease (3CLpro): Validation as a Molecular Target, Proposal of a Novel Catalytic Mechanism, and Inhibitors in Preclinical and Clinical Trials" Preprints. https://doi.org/10.20944/preprints202405.0326.v1
Abstract
Proteases represent common targets in combating infectious diseases including COVID-19. The 3-chymotrypsin-like protease (3CLpro) is a validated molecular target for COVID-19 and it is key for developing potent and selective inhibitors for inhibiting viral replication of SARS-CoV-2. In this review, we discuss structural relationships and diverse subsites of 3CLpro, shedding light on the pivotal role of dimerization and active site architecture in substrate recognition and catalysis. Our analysis of bioinformatics and other published studies unveil a proposal of a novel catalytic mechanism for the SARS-CoV-2 polyprotein cleavage by 3CLpro, centering on the triad mechanism involving His41-Cys145-Asp187 and its indispensable role in viral replication. Recognizing Asp187 as a crucial component in the catalytic process underscores its significance as a fundamental pharmacophoric element in drug design. Next, we provide an overview of both covalent and non-covalent inhibitors, elucidating advancements in drug development observed in preclinical and clinical trials. By highlighting various chemical classes and their pharmacokinetic profiles, our review aims to guide future research directions toward the development of highly selective inhibitors, underscore the significance of 3CLpro as a validated therapeutic target, and propel the progression of drug candidates through preclinical and clinical phases.
Keywords
SARS-CoV-2; 3CLpro; Novel Mechanism of Catalysis; FDA-approved drugs; Triad
Subject
Medicine and Pharmacology, Pharmacology and Toxicology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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