Crystallographic fragment screening and deep mutational scanning of Zika virus NS2B-NS3 protease enable development of resistance-resilient inhibitors.

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. 47 fragments with diverse scaffolds were 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 performed deep mutational scanning of NS2B-NS3 protease. Merging fragment hits yields an extensive set of 'mergers

SUBMITTER: Ni X 

PROVIDER: S-EPMC11092485 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature