ArticleNature communications2025
Combined crystallographic fragment screening and deep mutational scanning enable discovery of Zika virus NS2B-NS3 protease inhibitors.
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 9 papers.
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9 citing papers in PubMed.
- Physical priors improve performance of structure-based binding affinity models.bioRxiv : the preprint server for biology · 2026Article
- Scanning the horizon: deep mutational scanning approaches in virology.Journal of virology · 2026Review
- An inactive Zika NS2B-NS3pro protease construct for investigating allosteric inhibitors.Journal of structural biology · 2026Article
- Comparative analysis of deep mutational scanning datasets in enteroviruses A and B identifies functional divergence and therapeutic targets.Nature ecology & evolution · 2026Article
- Zika NS2B Protein: In Vitro Formation of Large Multimeric Networks.International journal of molecular sciences · 2026Article
- Crystal structure of fatty acid thioesterase A bound by 129 fragments provides diverse development opportunities.Pest management science · 2026Article
- The implications of FASN in viral infection and related diseases: a promising target in antiviral therapies.Frontiers in cellular and infection microbiology · 2026Review
- Coevolutionary constraints of Zika virus nonstructural protein 5 replication and interferon antagonism activities.bioRxiv : the preprint server for biology · 2025Article
- How many crystal structures do you need to trust your docking results?bioRxiv : the preprint server for biology · 2025Article
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Abstract
The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 46 fragments with diverse scaffolds are identified to bind in the active site of the protease, with another 6 fragments observed in a potential allosteric site. To identify binding sites that are intolerant to mutation and thus suppress the outgrowth of viruses resistant to inhibitors developed from bound fragments, we perform deep mutational scanning of the NS2B-NS3 protease. Merging fragment hits yields an extensive set of 'mergers', defined as synthetically accessible compounds that recapitulate constellations of observed fragment-protein interactions. In addition, the highly sociable fragment hits enable rapid exploration of chemical space via algorithmic calculation and thus yield diverse possible starting points. In this work, we maximally explore the binding opportunities to NS2B-NS3 protease, facilitating its resistance-resilient antiviral development.
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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.