Seasonal influenza is an infectious disease generally caused by Influenza Group A viruses and is known to have a high morbidity and mortality rate. Current treatments are limited to vaccinations and some small molecule inhibitors such as baloxavir marboxil and oseltamivir. Their mechanisms of action are endonuclease and neuraminidase inhibition, respectively. However, due to rapid mutations in the virus, new vaccines need to be developed yearly, and many influenza A isolates have shown resistance to approved therapeutics. Additionally, the circulating strains of the virus are not always consistent with the developed vaccine; therefore, there is a need for new therapeutic treatments. Hemagglutinin (HA) is a glycoprotein located on the surface of the viral particle and is known to be responsible for viral entry into host cells. Using a high-throughput screen of a Chembridge Small Molecule Library (~19,200 compounds), our group discovered a novel small molecule entry inhibitor (M726-0025) for HA. The inhibitor displayed micromolar activity without cytotoxicity in representative Group 1 (H5N1) and Group 2 (H7N1) influenza A pseudoviruses. A high-resolution X-ray crystal structure of H5N1 HA in conjugation with an entry inhibitor (CBS1117) guided optimization of the scaffold. We synthesized a focused library of hit compound analogs to improve the potency of the hit compound. Moving forward, we will profile the library for ADMET properties with the goal of improving the potency and drug-like characteristics of the hit compound.

Identification and optimization of novel influenza A entry inhibitors targeting group 1 and group 2 hemagglutinin

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ACS Fall 2022

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