ArticleCommunications medicine2025
Targeted protein degraders of SARS-CoV-2 Mpro are more active than enzymatic inhibition alone with activity against nirmatrelvir resistant virus.
Article in Communications medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Structure-based macrocyclization of α-ketoamides leads to potent inhibitors of coronaviral and enteroviral proteases.Communications chemistry · 2026Article
- Proof of concept: targeted protein degradation of the stress granules component G3BP1 as an antiviral strategy against norovirus infection.Antimicrobial agents and chemotherapy · 2026Article
- Degraders of the dengue virus capsid protein exhibit differentiated pharmacology relative to capsid inhibitors.Nature communications · 2026Article
- Integrated computational screen and validation of thalidomide-based PROTACs targeting SARS-CoV-2 main protease.RSC medicinal chemistry · 2026Article
- Innovative Strategies for the Targeted Degradation of Viral Proteins: Paving the Way for Next-Generation Therapeutics.Pharmaceutics · 2025Review
- PROteolysis TArgeting Chimeras (PROTACs) and beyond: targeted degradation as a new path to fight microbial pathogens.FEMS microbiology reviews · 2025Review
- Proteome-wide characterization of PTMs reveals host cell responses to viral infection and identifies putative antiviral drug targets.Frontiers in immunology · 2025Review
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Authors and funding
15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundEffective antiviral therapy is lacking for most viral infections, and when available, is frequently compromised by the selection of resistance. Targeted protein degraders could provide an avenue to more effective antivirals, able to overcome the selection of resistance. The aim of this study was to determine whether adaptation of SARS-CoV-2 main protease (Mpro, also described as chymotrypsin-like protease (3CL
methodsWe adapted the clinically approved Mpro inhibitor nirmatrelvir into a panel of degraders. Size-matched non-degrading controls were also synthesised to discriminate degradation activity from inhibition activity. Degrader activity was confirmed using an inducible Mpro-HiBiT tag expressing cell line. Antiviral activity against both wildtype and nirmatrelvir-resistant virus was performed using infection of susceptible cell lines.
resultsHere we show three compounds, derived from nirmatrelvir and utilising VHL or IAP ubiquitin ligase recruiters, capable of degrading Mpro protein in a concentration, time and proteasome dependent fashion. These compounds also degrade nirmatrelvir-resistant mutant Mpro. The most potent of these compounds possesses enhanced antiviral activity against multiple wildtype SARS-CoV-2 strains and nirmatrelvir-resistant strains compared to non-degrading controls.
conclusionsThis work demonstrates the feasibility of generating degraders from viral protein inhibitors, and confirms that degraders possess higher antiviral potency and activity against resistant virus, compared to size matched non-degrading enzymatic inhibitors. These findings further support the development of targeted viral protein degraders as antiviral drugs, which may lead to more effective antiviral therapies for the future.
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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 Socratic graph.