ArticleThe Journal of antimicrobial chemotherapy2015
ST-246 is a key antiviral to inhibit the viral F13L phospholipase, one of the essential proteins for orthopoxvirus wrapping.
Article in The Journal of antimicrobial chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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67 citing papers in PubMed, 111 citations in OpenAlex.
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- Structural and dynamic insights into F13L variations in monkeypox virus and their impact on tecovirimat resistance.Virology journal · 2025Article
- Development of a replication-defective mpox virus platform for fundamental and therapeutic research.Nature communications · 2025Article
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- 3D-EDiffMG: 3D equivariant diffusion-driven molecular generation to accelerate drug discovery.Journal of pharmaceutical analysis · 2025Article
- Novel derivatives of brincidofovir and (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine inhibit orthopoxviruses and human adenoviruses more potently than brincidofovir.Signal transduction and targeted therapy · 2025Article
- Structural insights into tecovirimat antiviral activity and poxvirus resistance.Nature microbiology · 2025Article
- Article
- AI-assisted identification of a novelBiosafety and health · 2025Article
- Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance.Viruses · 2025Article
- Review
- Notes from the Field: Mpox Cluster Caused by Tecovirimat-Resistant Monkeypox Virus - Five States, October 2023-February 2024.MMWR. Morbidity and mortality weekly report · 2024Article
- Mpox Recurrence and Tecovirimat Resistance in a Patient With Advanced Human Immunodeficiency Virus Disease.Open forum infectious diseases · 2024Article
7 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
objectivesST-246 is one of the key antivirals being developed to fight orthopoxvirus (OPV) infections. Its exact mode of action is not completely understood, but it has been reported to interfere with the wrapping of infectious virions, for which F13L (peripheral membrane protein) and B5R (type I glycoprotein) are required. Here we monitored the appearance of ST-246 resistance to identify its molecular target.
methodsVaccinia virus (VACV), cowpox virus (CPXV) and camelpox virus (CMLV) with reduced susceptibility to ST-246 were selected in cell culture and further characterized by antiviral assays and immunofluorescence. A panel of recombinant OPVs was engineered and a putative 3D model of F13L coupled with molecular docking was used to visualize drug-target interaction. The F13L gene of 65 CPXVs was sequenced to investigate F13L amino acid heterogeneity.
resultsAmino acid substitutions or insertions were found in the F13L gene of six drug-resistant OPVs and production of four F13L-recombinant viruses confirmed their role(s) in the occurrence of ST-246 resistance. F13L, but not B5R, knockout OPVs showed resistance to ST-246. ST-246 treatment of WT OPVs delocalized F13L- and B5R-encoded proteins and blocked virus wrapping. Putative modelling of F13L and ST-246 revealed a probable pocket into which ST-246 penetrates. None of the identified amino acid changes occurred naturally among newly sequenced or NCBI-derived OPV F13L sequences.
conclusionsBesides demonstrating that F13L is a direct target of ST-246, we also identified novel F13L residues involved in the interaction with ST-246. These findings are important for ST-246 use in the clinic and crucial for future drug-resistance surveillance programmes.
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