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Influenza RNA-dependent RNA polymerase (RdRp) Inhibitors
SRI is developing a new therapeutic agent for influenza virus infections.
SRI’s Webb Laboratory is developing a safe, effective new therapeutic agent for influenza virus infections that works by blocking influenza polymerase—a unique influenza protein critical for virus replication and infection.
Our work builds on the discovery of new active molecules found by the screening of targeted libraries with innovative influenza polymerase assays. The active molecules that were initially discovered were further developed into new drug-like molecules that are about 100 times more potent in the inhibition of influenza polymerase.
SRI plans to further develop these compounds into optimized drug leads through additional cycles of library synthesis and directed medicinal chemistry. These lead compounds can then be transferred to a biotech or pharmaceutical partner that will be responsible for development, clinical trials, and distribution of the new first-in-class influenza drug.
Major innovations associated with this work include:
- Our original observation regarding the mechanistic similarity between the two-metal binding site of HIV integrase (a clinically validated target) and influenza endonuclease. This led to our novel hypothesis that the pharmacophore of these two mechanistically similar sites should share useful common features for targeted library design.
- The novel specific design and associated development of the high-throughput chemistry that allowed for the synthesis of a library of 5,992 new compounds that target the two-metal binding site pharmacophore.
- Our extension of the internally developed IRdRp mini-genome (replicon) assay that allows for the targeted screening of >10,000 compounds.
- Design and development of a completely novel in vitro fluorescent polarization (FP) binding assay using a fluorescently labeled known inhibitor of endonuclease and a recombinant PAn endonuclease subunit as the key reagents.
- Our discovery of novel drug-like compounds that show good cell-based inhibition in the IRdRp replicon assay and also binding in the FP endonuclease assay.
- Our demonstration that binding in the above FP assay correlates with the published enzyme inhibition for a set of known inhibitors of native influenza endonuclease.
- Development of a new recombinant PAN construct that has given some of the first published co-crystal structures of an inhibitor with PAN.
Image credit: DuBois RM, Slavish PJ, Baughman BM, Yun M-K, Bao J, Webby RJ, Webb TR and White SW. Structural and Biochemical Basis for Development of Influenza Virus Inhibitors Targeting the PA Endonuclease. PLoS Pathog (2012) 8(8): e1002830. doi:10.1371/journal.ppat.1002830.
Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R01AI098757. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.