ArticleScience advances2020
Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design.
Article in Science advances, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 283 papers.
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Who cites it
283 citing papers in PubMed.
- Hitting Coronaviruses Where It Hurts: Antiviral Strategies Targeting Viral Proteins.ChemMedChem · 2026Review
- Substrate-Selective Inhibition of the SARS-CoV-2 Papain-Like Protease: Inhibition of Hydrolysis of Human Over Viral Substrates.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- Antimicrobial peptides as computational candidates for SARS-CoV-2 papain-like protease inhibition.Scientific reports · 2026Article
- Discovery of novel druggable binding pockets on SARS-CoV-2 PLpro via fragment screening and insights for structure-based inhibitor design.The Journal of biological chemistry · 2026Article
- Structural analysis of the flexibility of the Ubl2 domain within the papain-like protease of SARS-CoV-2.Acta crystallographica. Section F, Structural biology communications · 2026Article
- Discovery of the SARS-CoV-2 Papain-Like Protease Inhibitor MR1-114: From Structure-Based Design toJournal of medicinal chemistry · 2026Article
- Unlocking the secrets of SARS-CoV-2 nsp3 by combining experiments with AlphaFold2 domain prediction.Life science alliance · 2026Article
- Metabolites from South African Medicinal Plants as Dual-Function Inhibitors of the SARS-CoV-2 Papain-like Protease (PLLife (Basel, Switzerland) · 2026Article
- Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease.Journal of medicinal chemistry · 2026Article
- Structural Basis and Inhibitor Development of SARS-CoV-2 Papain-like Protease.Molecules (Basel, Switzerland) · 2026Review
- YL1004 is a SARS-CoV-2 papain-like protease inhibitor with immunomodulatory and antiviral activity in mice.Nature communications · 2026Article
- Discovery of Fragment-Based Inhibitors of SARS-CoV-2 PLJournal of medicinal chemistry · 2026Article
- Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models.Journal of medicinal chemistry · 2026Article
- Chasing allosteric inhibition of the SARS-CoV-2 PLpro via molecular dynamics simulations with flooding fragments (MDFFr).Journal of computer-aided molecular design · 2025Article
- Article
- Exploring Nirmatrelvir Derivatives Through P2 Substituent Modifications and Warhead Innovations Targeting the Main Protease of SARS-CoV-2.Archiv der Pharmazie · 2025Article
- 1,2,4-Thiadiazolidin-3,5-Diones as Inhibitors of Cysteine Proteases.Molecules (Basel, Switzerland) · 2025Article
- Integrating Molecular Dynamics, Molecular Docking, and Machine Learning for Predicting SARS-CoV-2 Papain-like Protease Binders.Molecules (Basel, Switzerland) · 2025Article
- Structure-Based Design and In-Silico Evaluation of Computationally Proposed Curcumin Derivatives as Potential Inhibitors of the Coronaviral PLpro Enzymes.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Identification of naturally occurring drug-resistant mutations of SARS-CoV-2 papain-like protease.Nature communications · 2025Article
223 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors.
Funding
Abstract
Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library and performed comprehensive activity profiling of SARS-CoV-2 PLpro. On the scaffold of the best hits from positional scanning, we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro. We determined crystal structures of two of these inhibitors in complex with SARS-CoV-2 PLpro that reveals their inhibitory mechanisms and provides a molecular basis for the observed substrate specificity profiles. Last, we demonstrate that SARS-CoV-2 PLpro harbors deISGylating activity similar to SARSCoV-1 PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Together, this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repurposing.
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