Fragment-Based Identification of Influenza Endonuclease Inhibitors.
The influenza virus is responsible for millions of cases of severe illness annually. Yearly variance in the effectiveness of vaccination, coupled with emerging drug resistance, necessitates the development of new drugs to treat influenza infections. One attractive target is the RNA-dependent RNA polymerase PA subunit. Herein we report the development of inhibitors of influenza PA endonuclease derived from lead compounds identified from a metal-binding pharmacophore (MBP) library screen. Pyromeconic acid and derivatives thereof were found to be potent inhibitors of endonuclease. Guided by modeling and previously reported structural data, several sublibraries of molecules were elaborated from the MBP hits. Structure-activity relationships were established, and more potent molecules were designed and synthesized using fragment growth and fragment merging strategies. This approach ultimately resulted in the development of a lead compound with an IC50 value of 14 nM, which displayed an EC50 value of 2.1 μM against H1N1 influenza virus in MDCK cells.
Department of Chemistry and Biochemistry, University of California, San Diego , La Jolla, California 92093, United States.
Cy V
CV
Credille
Department of Chemistry and Biochemistry, University of California, San Diego , La Jolla, California 92093, United States.
Yao
Y
Chen
Department of Chemistry and Biochemistry, University of California, San Diego , La Jolla, California 92093, United States.
Seth M
SM
Cohen
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology*; D061985:Madin Darby Canine Kidney Cells; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; C061290:PA protein, influenza viruses; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase