Flu

Biography

Biography: Vadim Bichko

Abstract

This study is focused on the discovery and development of new oral small molecule influenza neuraminidase inhibitors, active against Oseltamivir-resistant virus strains. A number of compounds was designed, synthesized and evaluated for antiviral properties in vitro and in vivo. A 3D Molecular docking, assisted by a pharmacophore model, was applied to rank compounds within different series by the predicted antiviral potency. The most promising compound, AV5080[(3R,4R,5S) 5-[(diaminomethylene)amino] 3-(1-ethylpropoxy) 4[(fluoroacetyl)amino]cyclohex-1-ene-1-carboxylic acid], is currently in pre-clinical development for treatment of influenza. This compound was stable in rat, dog and human plasma (>93% remaining after 24 h). AV5080 demonstrated picomolar activity against influenza neuraminidase in vitro, similar or better than Oseltamivir (the IC50 values of 0.03 nM and 0.07 nM against NA of A/duck/Minnesota/1525/1981, H5N1, and A/ Perth/265/2009, H1N1, 275H, respectively). In the influenza-infected cultured MDCK cells, this compound demonstrated high potency against influenza strains A and B (EC90 = 0.71±0.24 nM, 28 times lower than that for Oseltamivir against A/California/07/2009/H1N1 isolate). Most importantly, AV5080 was highly active against Oseltamivir-resistant influenza strains. The efficacy of AV5080 in mice, challenged with a lethal dose of A/Aichi/2/1969/H3N2 isolate, was similar to that of Oseltamivir (90% and 100% survival rate at 25 mg/kg dose). In the safety pharmacology studies with AV5080 in vitro and in vivo (AMES test, chromosomal aberration, hERG test), no signs of geno-or cardiotoxicity was observed. In summary, AV5080 is a promising novel oral drug candidate for treatment of influenza, including Oseltamivir-resistant virus strains. Further preclinical development of AV5080 is warranted.