Abstract by Gregory Mohl
Chemistry and Biochemistry
In Silico Discovery of Influenza Polymerase Inhibitors
Resistance makes the influenza virus a difficult target for antiviral development. M2 blockers are ineffective against most strains due to point mutations in the M2 channel. Neuraminidase inhibitors are also vulnerable to resistance, highlighting the need for antivirals that inhibit infection by a new mechanism. Novel Influenza inhibitors were identified using a high-throughput virtual screen of a protein-protein interaction inhibitor library. Three of the compounds purchased from this library inhibited Influenza protein synthesis. Variants of the top compound were synthesized and characterized, and several compounds were identified with nanomolar inhibition of Influenza protein synthesis. Three of these derivatives protected MDCK cells against Influenza A and B in the CPE assay. Viral resistance develops slowly, suggesting that these inhibitors target a key, conserved binding site.