ArticleCell discovery2024
Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04.
Article in Cell discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06197217 (A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Clinical Trial Evaluating the Efficacy and Safety of WPV01 in Patients With Mild to Moderate COVID-19), which is not on this map. Cited by 11 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Clinical Trial Evaluating the Efficacy and Safety of WPV01 in Patients With Mild to Moderate COVID-19
Who cites it
11 citing papers in PubMed, 24 citations in OpenAlex.
- Human angiotensin‑converting enzyme 2‑specific benzothiazole-based allosteric inhibitor against pan‑sarbecoviruses.Nature communications · 2026Article
- Mutation-Induced Resistance of SARS-CoV-2 MInternational journal of molecular sciences · 2026Article
- Screening-Identified Oxazole-4-Carboxamide KB-2777 Exhibits In Vitro Anti-Coronavirus Activity.Pharmaceutics · 2025Article
- Characterization of an unusual SARS-CoV-2 main protease natural variant exhibiting resistance to nirmatrelvir and ensitrelvir.Communications biology · 2025Article
- Article
- A general and biomedical perspective of viral quasispecies.RNA (New York, N.Y.) · 2025Review
- The Batalogue: an overview of betacoronaviruses with future pandemic potential.FEMS microbiology reviews · 2025Review
- Optimization of SARS-CoV-2 MInternational journal of molecular sciences · 2025Article
- Replication capacity and susceptibility of nirmatrelvir-resistant mutants to next-generation Mpro inhibitors in a SARS-CoV-2 replicon system.Antiviral research · 2024Article
- Review
- Arylamines QSAR-Based Design and Molecular Dynamics of New Phenylthiophene and Benzimidazole Derivatives with Affinity for the C111, Y268, and H73 Sites of SARS-CoV-2 PLpro Enzyme.Pharmaceuticals (Basel, Switzerland) · 2024Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro's C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.