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Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx-enabled high-throughput medicinal chemistry.
- Source :
-
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. - Publication Year :
- 2024
-
Abstract
- 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 <subscript>50</subscript> 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.<br />Competing Interests: Competing interests statement:The authors declare no competing interest.
- Subjects :
- Humans
Chemistry, Pharmaceutical methods
High-Throughput Screening Assays methods
Influenza, Human drug therapy
Influenza, Human virology
Crystallography, X-Ray methods
Click Chemistry methods
Animals
Influenza A virus drug effects
Madin Darby Canine Kidney Cells
Viral Fusion Protein Inhibitors pharmacology
Viral Fusion Protein Inhibitors chemistry
Dogs
Hemagglutinin Glycoproteins, Influenza Virus metabolism
Hemagglutinin Glycoproteins, Influenza Virus chemistry
Antiviral Agents pharmacology
Antiviral Agents chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 121
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 38753503
- Full Text :
- https://doi.org/10.1073/pnas.2310677121