Analysis of Structures of SARS-CoV-2 Papain-like Protease Bound with Ligands Unveils Structural Features for Inhibiting the Enzyme.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

SARS-CoV-2*/enzymology ; SARS-CoV-2*/drug effects ; Coronavirus Papain-Like Proteases*/chemistry ; Coronavirus Papain-Like Proteases*/antagonists & inhibitors ; Coronavirus Papain-Like Proteases*/metabolism; Ligands ; Humans ; Binding Sites ; COVID-19 Drug Treatment ; Protein Binding ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protease Inhibitors/metabolism ; COVID-19/virology ; Models, Molecular ; Coronavirus 3C Proteases/antagonists & inhibitors ; Coronavirus 3C Proteases/chemistry ; Coronavirus 3C Proteases/metabolism

The COVID-19 pandemic, driven by the novel coronavirus SARS-CoV-2, has drastically reshaped global health and socioeconomic landscapes. The papain-like protease (PLpro) plays a critical role in viral polyprotein cleavage and immune evasion, making it a prime target for therapeutic intervention. Numerous compounds have been identified as inhibitors of SARS-CoV-2 PLpro, with many characterized through crystallographic studies. To date, over 70 three-dimensional (3D) structures of PLpro complexed ligands have been deposited in the Protein Data Bank, offering valuable insight into ligand-binding features that could aid the discovery and development of effective COVID-19 treatments targeting PLpro. In this study, we reviewed and analyzed these 3D structures, focusing on the key residues involved in ligand interactions. Our analysis revealed that most inhibitors bind to PLpro's substrate recognition sites S3/S4 and SUb2. While these sites are highly attractive and have been extensively explored, other potential binding regions, such as SUb1 and the Zn(II) domain, are less explored and may hold untapped potential for future COVID-19 drug discovery and development. Our structural analysis provides insights into the molecular features of PLpro that could accelerate the development of novel therapeutics targeting this essential viral enzyme.

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Keywords: 3D structures; PLpro; SARS CoV-2; binding sites; ligands; papain-like protease

0 (Ligands)
EC 3.4.22.2 (papain-like protease, SARS-CoV-2)
EC 3.4.22.2 (Coronavirus Papain-Like Proteases)
0 (Antiviral Agents)
0 (Protease Inhibitors)
EC 3.4.22.28 (Coronavirus 3C Proteases)

Date Created: 20250213 Date Completed: 20250213 Latest Revision: 20250215

20250215

PMC11820935

10.3390/molecules30030491

39942596