Virology & Mycology
Open Access

Targeting the influenza RNA-dependent RNA polymerase

2^nd International Conference on Flu

October 31-November 02, 2016 San Francisco, USA

Diane Beylkin

SRI International, USA

Scientific Tracks Abstracts: Virol Mycol

Abstract :

Influenza is an infectious disease responsible for up to 500000 deaths worldwide annually despite the availability of vaccines and antiviral drugs. Vaccines target the most common strains of the virus, leaving those exposed to other strains at risk for infection. Most small molecule antiviral drugs currently on the market act as neuraminidase inhibitors (zanamivir, oseltamivir, peramivir) or target the M2-ion channel (amantadine, rimantadine); however, due to the lack of viral proof-reading enzymes, these targets are prone to rapid mutations that often confer antiviral resistance. In contrast, the viral RNA-dependent RNA polymerase (RdRp) is an attractive drug target because it is relatively slow to develop drug resistance, conserved across genotypes and essential to viral replication. With no eukaryotic homologue, the potential for toxicity due to off-target effects is low for RdRp targeting compounds. Our research focuses on targeting the endonuclease domain of the RdRp, located on the PA N-terminal domain, which has a two metal binding active site. We have developed a series of 2-substituted dihydroxypyrimidine carboxamides which bind to the endonuclease active site and disrupt its activity in vitro. The activity of these compounds has been validated by fluorescent polarization binding assays and plaque inhibition assays. The most potent inhibitors have been co-crystallized with PAN to determine the structure-activity relationships, allowing us to improve their efficacy. We will discuss the structure-activity relationship of our analogs and several interesting protein-small molecule X-ray crystal structures, as well as our progress on the development of an innovative therapeutic lead compound targeting influenza endonuclease.

Biography :

Diane Beylkin was graduated with honors from Caltech in 2010 with a BS degree in Chemistry. She has recently completed her PhD at Yale University in the laboratory of Dr. Andrew Phillips working on the total synthesis of thailandamide A. She is currently conducting Postdoctoral research on the influenza virus at SRI International in the laboratory of Dr. Thomas Webb.

Email: diane.beylkin@sri.com