The influenza virus is responsible for annual seasonal illness, resulting in between 250,000 and 500,000 deaths worldwide. The last century alone has seen the advent of four influenza pandemics, each resulting in over one million deaths. While vaccinations can be a reasonable prophylactic for healthy adults, they are less effective for individuals with compromised immunity. The efficacy of these vaccines is also heavily dependent on correctly predicting the predominant infectious strains for any one year, and incorrect predictions can render vaccination less than 30% effective. Existing drugs, such as Relenza (zanamivir; GSK) and Tamiflu (oseltamivir; Roche) which target viral neuraminidase can be useful in treating influenza infections, but must be administered within 1-2 days of infection to be effective and have many undesirable side-effects. Considering this, there is an urgent need for the development of new drugs to prevent and treat influenza infection.<br/>One attractive target for viral inhibition is the endonuclease portion of the PA subunit of the viral RNA-dependent RNA polymerase, which mediates viral 5’ cap-snatching. This target is a dinuclear Mn<sup>2+</sup> metalloenzyme that lacks a human counterpart. Herein we report the development of novel inhibitors of influenza endonuclease derived from lead compounds identified in a targeted metal-binding pharmacophore (MBP) library screen. Using a FRET-labeled DNA oligonucleotide substrate, we measured the endonuclease activity of the PA subunit of H1N1 influenza A in the presence of MBP molecules, and identified more than 10 molecules with IC50 values of &lt;10 µM from a library of 250 compounds. Guided by modeling, a modest sublibrary of molecules was elaborated from the MBP hits. These lead-like molecules were synthesized and tested for activity. Structural-activity relationships were established, and more potent molecules were designed and synthesized using fragment growth and fragment merging strategies. This has resulted in the development of several lead molecules with nanomolar in vitro inhibitory activity (IC50 &lt;100 nM) against viral PA endonuclease.

Potent influenza endonuclease inhibitors developed from metal-binding pharmacophore library screen

251st National Meeting (2016)

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