ArticleNature communications2025
A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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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.
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Who cites it
20 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
- Conformational Dynamics of Viral Protease Precursors in Maturation, Inhibition, and Drug-Resistance Development.Viruses · 2026Review
- 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
- Longitudinal analysis reveals myeloid cell contributions to murine neuroPASC pathogenesis.Nature communications · 2026Article
- Targeting SARS-CoV-2 Non-Structural Proteins: A Blueprint for Next-Generation Small-Molecule Coronavirus Antivirals.Pharmaceutics · 2026Review
- Extending the Targets for Coronavirus Antivirals Beyond That of Approved Drugs: Insights From Preclinical Research.Microbial biotechnology · 2026Review
- Nicotine-Inspired, De Novo-Designed SARS-CoV-2 Main Protease Inhibitors Reveal Unique Chemistry for Covalently Conjugating Both Cysteine and Histidine Residues in the Catalytic Dyad.Journal of the American Chemical Society · 2026Article
- Discovery of the SARS-CoV-2 Papain-Like Protease Inhibitor MR1-114: From Structure-Based Design toJournal of medicinal chemistry · 2026Article
- Computational proteomics to enhance personalized treatment of COVID-19 and Long COVID.Clinical proteomics · 2026Review
- 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 SARS-CoV-2 PLpro inhibitors and RIPK1 inhibitors with synergistic antiviral efficacy in a mouse COVID-19 model.Acta pharmaceutica Sinica. B · 2026Article
- Non-apoptotic caspase-8 is critical for orchestrating exaggerated inflammation during severe SARS-CoV-2 infection.Nature communications · 2025Article
- SARS-CoV‑2 Papain-Like Protease Inhibitors Based on Naphthalen-1-ylethanamine and Halogenated Benzene Moieties.ACS omega · 2025Article
- Screening of Medicines for Malaria Venture Open Boxes Identifies Potent SARS-CoV‑2 Papain-like Protease (PLACS omega · 2025Article
- Divergent resistance pathways amongst SARS-CoV-2 PLpro inhibitors highlight the need for scaffold diversity.PLoS pathogens · 2025Article
- Review
- 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
- Article
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Authors and funding
43 authors.
Funding
Abstract
The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has highlighted the vulnerability of a globally connected population to zoonotic viruses. The FDA-approved coronavirus antiviral Paxlovid targets the essential SARS-CoV-2 main protease, Mpro. Whilst effective in the acute phase of a COVID infection, Paxlovid cannot be used by all patients, can lead to viral recurrence, and does not protect against post-acute sequelae of COVID-19 (PASC), commonly known as long COVID, an emerging significant health burden that remains poorly understood and untreated. Alternative antivirals that are addressing broader patient needs are urgently required. We here report our drug discovery efforts to target PLpro, a further essential coronaviral protease, for which we report a novel chemical scaffold that targets SARS-CoV-2 PLpro with low nanomolar activity, and which exhibits activity against PLpro of other pathogenic coronaviruses. Our lead compound shows excellent in vivo efficacy in a mouse model of severe acute disease. Importantly, our mouse model recapitulates long-term pathologies matching closely those seen in PASC patients. Our lead compound offers protection against a range of PASC symptoms in this model, prevents lung pathology and reduces brain dysfunction. This provides proof-of-principle that PLpro inhibition may have clinical relevance for PASC prevention and treatment going forward.
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