An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen

Proceedings of the National Academy of Sciences of the United States of America
Y. YaoDennis W. Wolan

Abstract

Influenza hemagglutinin (HA) glycoprotein is the primary surface antigen targeted by the host immune response and a focus for development of novel vaccines, broadly neutralizing antibodies (bnAbs), and therapeutics. HA enables viral entry into host cells via receptor binding and membrane fusion and is a validated target for drug discovery. However, to date, only a very few bona fide small molecules have been reported against the HA. To identity new antiviral lead candidates against the highly conserved fusion machinery in the HA stem, we synthesized a fluorescence-polarization probe based on a recently described neutralizing cyclic peptide P7 derived from the complementarity-determining region loops of human bnAbs FI6v3 and CR9114 against the HA stem. We then designed a robust binding assay compatible with high-throughput screening to identify molecules with low micromolar to nanomolar affinity to influenza A group 1 HAs. Our simple, low-cost, and efficient in vitro assay was used to screen H1/Puerto Rico/8/1934 (H1/PR8) HA trimer against ∼72,000 compounds. The crystal structure of H1/PR8 HA in complex with our best hit compound F0045(S) confirmed that it binds to pockets in the HA stem similar to bnAbs FI6v3 and CR9114, cyclic...Continue Reading

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Citations

Sep 26, 2020·Viruses·Nicholas C Wu, Ian A Wilson
Dec 17, 2020·Sensors·Olga D HendricksonSergei A Eremin
Apr 23, 2021·Scientific Reports·Yu-Jen ChangChih-Hao Lu
Jul 3, 2021·Pharmaceuticals·Zhaoyu ChenRuikun Du
Jul 15, 2021·Journal of Medicinal Chemistry·Kris WhiteBeatriz M A Fontoura
Jul 2, 2021·Annual Review of Virology·Han-Yuan Liu, Priscilla L Yang

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Methods Mentioned

BETA
glycosylation
enzyme-linked
AlphaLISA
X-ray
Assay
electrophoresis
surface plasmon resonance

Software Mentioned

COOT
GraphPad Prism
Phenix
Lidia
MacPyMol
AlphaLISA
ChemDraw Ultra
Flatland Ligand Environment View

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