ArticleNature communications2024
Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
What it found
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Who cites it
12 citing papers in PubMed.
- 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
- Host OTUB2 and viral PLpro stabilize NSP8 to promote SARS-CoV-2 replication.Virologica Sinica · 2026Article
- Machine learning framework for cost effective deep mutational scanning through targeted substitution profiling.BMC bioinformatics · 2026Article
- Structural Basis and Inhibitor Development of SARS-CoV-2 Papain-like Protease.Molecules (Basel, Switzerland) · 2026Review
- Computational design of 3C-like protease substrate peptide for modular detection of protease activity of coronavirus.Engineering in life sciences · 2026Article
- Identification of a Quinolone-Based Scaffold as a Dual SARS-COV-2 PLᵖʳᵒ and Mᵖʳᵒ Inhibitor: An Integrated Molecular Modeling and In-vitro Evaluation Approach.Drug design, development and therapy · 2026Article
- Insights from deep mutational scanning in the context of an emerging pathogen.Biochemical Society transactions · 2025Review
- Divergent resistance pathways amongst SARS-CoV-2 PLpro inhibitors highlight the need for scaffold diversity.PLoS pathogens · 2025Article
- Dissecting the effects of single amino acid substitutions in SARS-CoV-2 Mpro.Protein science : a publication of the Protein Society · 2025Article
- Strategies and efforts in circumventing the emergence of antiviral resistance against conventional antivirals.npj antimicrobials and resistance · 2025Review
- A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID.Nature communications · 2025Article
- Analysis of Structures of SARS-CoV-2 Papain-like Protease Bound with Ligands Unveils Structural Features for Inhibiting the Enzyme.Molecules (Basel, Switzerland) · 2025Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Papain-like protease (PLpro) is an attractive drug target for SARS-CoV-2 because it is essential for viral replication, cleaving viral poly-proteins pp1a and pp1ab, and has de-ubiquitylation and de-ISGylation activities, affecting innate immune responses. We employ Deep Mutational Scanning to evaluate the mutational effects on PLpro enzymatic activity and protein stability in mammalian cells. We confirm features of the active site and identify mutations in neighboring residues that alter activity. We characterize residues responsible for substrate binding and demonstrate that although residues in the blocking loop are remarkably tolerant to mutation, blocking loop flexibility is important for function. We additionally find a connected network of mutations affecting activity that extends far from the active site. We leverage our library to identify drug-escape variants to a common PLpro inhibitor scaffold and predict that plasticity in both the S4 pocket and blocking loop sequence should be considered during the drug design process.
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