ArticleJournal of medicinal chemistry2022
Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity.
Article in Journal of medicinal chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 112 papers.
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112 citing papers in PubMed, 208 citations in OpenAlex.
- 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
- Recent Advances in the Design of Inhibitors Targeting the Viral Entry and Replication of the SARS-CoV-2 Virus, Driven by In Silico Approaches.Molecules (Basel, Switzerland) · 2026Review
- 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
- Enhanced Antiviral Activity of Novel Umifenovir Derivatives against SARS-CoV-2: Insights from an International Collaborative Study.ACS omega · 2026Article
- Discovery of the SARS-CoV-2 Papain-Like Protease Inhibitor MR1-114: From Structure-Based Design toJournal of medicinal chemistry · 2026Article
- Discovery of Spiro[chromane-2,4'-piperidine] Derivatives as Irreversible Inhibitors of SARS-CoV-2 Papain-like Protease.Journal of medicinal chemistry · 2026Article
- Mechanistic insights into the noncovalent inhibition of SARS-CoV-2 PLpro: a multiscale computational study.Journal of computer-aided molecular design · 2026Article
- Design, synthesis and activity evaluation of dual-target inhibitors against papain-like and main proteases of porcine epidemic diarrhea virus.Journal of advanced research · 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
- Affinity of drug candidates binding to SARS-CoV-2 PLpro assessed using a generalized-ensemble method.Scientific reports · 2026Article
- SARS-CoV‑2 Papain-Like Protease Inhibitors Based on Naphthalen-1-ylethanamine and Halogenated Benzene Moieties.ACS omega · 2025Article
- Selective Degradation and Inhibition of SARS-CoV-2 3CLInternational journal of molecular sciences · 2025Article
- Screening of Medicines for Malaria Venture Open Boxes Identifies Potent SARS-CoV‑2 Papain-like Protease (PLACS omega · 2025Article
- Enantioconvergent Chan-Lam Coupling: Synthesis of Chiral Benzylic Amides via Cu-Catalyzed Deborylative Amidation.Journal of the American Chemical Society · 2025Article
- Elucidation of a Parasitic Proton-Coupled Electron Transfer in a Photocatalytic Benzylic C-H Sulfonamidation.Organic letters · 2025Article
- PLpro Inhibitors as a Potential Treatment for COVID-19.Biomedicines · 2025Article
- Scutellaria barbata D. Don extracts alleviate SARS-CoV-2 induced acute lung injury by inhibiting virus replication and bi-directional immune modulation.Virologica Sinica · 2025Article
52 more citing papers are in PubMed but not listed here.
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13 authors at 2 institutions in 1 country.
Funding
Abstract
Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine. To overcome this challenge, we leveraged the cooperativity of multiple shallow binding sites on the PLpro surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed that ligand binding induces new interactions with PLpro: by closing of the BL2 loop of PLpro forming a novel "BL2 groove" and by mimicking the binding interaction of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity translates to the most potent PLpro inhibitors reported to date, with slow off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.
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