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A patent review of Mpro protease inhibitors for the treatment of COVID-19 infections (2020 - present).
Abstract
The SARS-CoV-2 main protease (Mpro, also known as 3CLpro or nsp5) is essential for viral replication. As there are no close human homologs, it represents an attractive and specific target for antiviral therapy against COVID-19. Its well-defined active site and conserved substrate specificity have enabled structure-guided drug design with high precision.
This review examines the patent landscape for small-molecule inhibitors of SARS-CoV-2 Mpro published between 2020 and early 2025. Compounds were grouped by scaffold type and mechanism of action, covering covalent and non-covalent inhibitors, orthosteric and allosteric binders and unique modalities such as PROTACs. Clinically advanced agents including nirmatrelvir, ensitrelvir, simnotrelvir, zevotrelvir and leritrelvir are highlighted alongside structurally novel leads and broad-spectrum candidates.
A number of Mpro inhibitors have progressed into preclinical and clinical stages, underscoring the rapid advancement in this field. The accumulation of structural knowledge, chemical diversity and mechanistic insight has laid a robust foundation for future antiviral development and may further enhance the utility of Mpro inhibitors against evolving coronaviruses.
This review examines the patent landscape for small-molecule inhibitors of SARS-CoV-2 Mpro published between 2020 and early 2025. Compounds were grouped by scaffold type and mechanism of action, covering covalent and non-covalent inhibitors, orthosteric and allosteric binders and unique modalities such as PROTACs. Clinically advanced agents including nirmatrelvir, ensitrelvir, simnotrelvir, zevotrelvir and leritrelvir are highlighted alongside structurally novel leads and broad-spectrum candidates.
A number of Mpro inhibitors have progressed into preclinical and clinical stages, underscoring the rapid advancement in this field. The accumulation of structural knowledge, chemical diversity and mechanistic insight has laid a robust foundation for future antiviral development and may further enhance the utility of Mpro inhibitors against evolving coronaviruses.
Description
Keywords
3CLpro, Mpro, SARS-CoV-2 main protease, antiviral drug discovery, covalent inhibitor, medicinal chemistry, non-covalent inhibitor, nsp5
Funding
Czech Science Foundation, project no. 21-39625; Austrian Science Fund, grant no. 10.55776/I5406; German Research Foundation, grant no. FE2166/1‐1
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Type
JournalArticle
License
Attribution 4.0 International
Date
2025-12-08
Publisher
Taylor & Francis
Book
Journal
Expert opinion on therapeutic patents
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DOI
10.1080/13543776.2025.2588773