Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like cysteine protease (PLpro) represents one of only two essential cysteine proteases involved in the regulation of viral replication. It, therefore, qualifies as a promising therapeutic target for the development of antiviral agents. We identified a previously synthesized protease inhibitor, resulting from an earlier project, as a PLpro inhibitor and crafted a structure-activity relationship around the hit, leading to the more potent inhibitors ZHAWOC6941 (17h) and ZHAWOC25153 (17o) displaying IC50 values of 8 and 7 µM, respectively. The two compounds represent a new class of PLpro inhibitors and, with single-digit micromolar IC50 values, are comparable to inhibitors found in the literature.
Keywords:
SARS‐CoV‐2; inhibitor; papain‐like protease; structure–activity relationship.
© 2024 Deutsche Pharmazeutische Gesellschaft.
MeSH terms
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Antiviral Agents* / chemical synthesis
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Antiviral Agents* / chemistry
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Antiviral Agents* / pharmacology
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COVID-19 Drug Treatment
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Coronavirus 3C Proteases / antagonists & inhibitors
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Coronavirus 3C Proteases / metabolism
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Coronavirus Papain-Like Proteases / antagonists & inhibitors
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Coronavirus Papain-Like Proteases / chemistry
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / chemistry
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Cysteine Proteinase Inhibitors / pharmacology
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Humans
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Inhibitory Concentration 50
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Phthalimides* / chemical synthesis
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Phthalimides* / chemistry
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Phthalimides* / pharmacology
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Protease Inhibitors / chemical synthesis
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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SARS-CoV-2* / drug effects
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SARS-CoV-2* / enzymology
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Structure-Activity Relationship
Substances
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Antiviral Agents
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Phthalimides
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Coronavirus Papain-Like Proteases
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Cysteine Proteinase Inhibitors
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Protease Inhibitors
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papain-like protease, SARS-CoV-2
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Coronavirus 3C Proteases