Structural investigation of Small Molecules Targeting Influenza A Virus Polymerase

Influenza (Flu) viruses are human respiratory pathogens, responsible for both seasonal epidemics and global pandemics. The currently available anti-Flu drugs, i.e., M2 blockers and neuraminidase inhibitors, are considered still inadequate and may become ineffective when resistant viral strains emerge.1 New antiviral strategies against Flu, with an innovative mechanism of action, are urgently needed. The viral RNA-dependent RNA polymerase (RdRP), and in particular its correct assembly to a heterotrimer formed by the subunits PB1, PB2, and PA, provides an underexploited drug target. Using the crystal structure of a truncated form of PA bound to a PB1-derived peptide,2 an in-silico screening of small molecule libraries recently identified some promising compounds able to specifically interfere with the PA-PB1 interaction.3,4 The inhibitory activity translated in the ability to block virus growth in cell cultures at non-cytotoxic concentrations, providing a proof-of-principle for this antiviral strategy that could present several advantages compared to the existing drugs. Starting from one of the most interesting hits, a series of analogues have been designed and synthesized with the aim to increase the PA/PB1 inhibitory activity and to achieve a potent anti-Flu activity also encompassing clinical isolates and drug-resistant strains. In this work, the structural optimization cycle that led to identify improved anti-Flu derivatives along with preliminary SAR information, will be presented.