Open AccessFragment-Based Identification of Influenza Endonuclease Inhibitors
Author(s) -
Cy V. Credille,
Yao Chen,
Seth M. Cohen
Publication year - 2016
Publication title -
journal of medicinal chemistry
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.6b00628
Subject(s) - pharmacophore , chemistry , endonuclease , lead compound , polymerase , influenza a virus , virus , structure–activity relationship , antiviral drug , enzyme , virology , computational biology , in vitro , biochemistry , biology
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.