Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx-enabled high-throughput medicinal chemistry
Year: 2024
Type: article
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 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.
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: U.S. Department of Energy, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Basic Energy Sciences, Biological and Environmental Research, Argonne National Laboratory, SLAC National Accelerator Laboratory
Awards: G102163711, G107546177, G1229526393, G1286251239, G1313983767, G1315549955, G1664757510, G1804828992, G1831385526, G2287611682, G2300450775, G2371548206, G262532246, G262962599, G2857925935, G303061748, G3075337988, G315621713, G3488436650, G3629260272, G409777406, G4235786860, G426311843, G4269941704, G4280418065, Console and probe upgrade for 600 MHz NMR, G4581610328, G477162814, G495301720, G498139845, G5097437870, G5387317844, G5505268400, G5570207115, G5607048534, G5723167349, G618388848, G6550344761, G6848031779, G6918803902, G7283024673, G7583137537, A Synchroton Radiation Structural Biology Resource, G8382000481, G8925327636, G9000069621, G9000108980, Cancer Center Support Grant, G911061179, G969889393, G993149817
OpenAlex ID: W4396950655