Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx-enabled high-throughput medicinal chemistry.

Autor: Kitamura S; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461., Lin TH; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037., Lee CD; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037., Takamura A; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037., Kadam RU; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037., Zhang D; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037., Zhu X; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037., Dada L; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461., Nagai E; Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461., Yu W; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037., Yao Y; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037., Sharpless KB; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037., Wilson IA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037., Wolan DW; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 May 28; Vol. 121 (22), pp. e2310677121. Date of Electronic Publication: 2024 May 16.
DOI: 10.1073/pnas.2310677121
Abstrakt: Seasonal and pandemic-associated influenza strains cause highly contagious viral respiratory infections that can lead to severe illness and excess mortality. Here, we report on the optimization of our small-molecule inhibitor F0045(S) targeting the influenza hemagglutinin (HA) stem with our Sulfur-Fluoride Exchange (SuFEx) click chemistry-based high-throughput medicinal chemistry (HTMC) strategy. A combination of SuFEx- and amide-based lead molecule diversification and structure-guided design led to identification and validation of ultrapotent influenza fusion inhibitors with subnanomolar EC 50 cellular antiviral activity against several influenza A group 1 strains. X-ray structures of six of these compounds with HA indicate that the appended moieties occupy additional pockets on the HA surface and increase the binding interaction, where the accumulation of several polar interactions also contributes to the improved affinity. The compounds here represent the most potent HA small-molecule inhibitors to date. Our divergent HTMC platform is therefore a powerful, rapid, and cost-effective approach to develop bioactive chemical probes and drug-like candidates against viral targets.
Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze: MEDLINE
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