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.