Our Scientific Approach:
Structure of amantadine (nitrogen in cyan and carbon in white) inside the binding site of M2 protein
(Figure adapted from Nature 2008, etc.)
Influmedix is using structure-based methods to intelligently design therapeutics for the various targets found in the influenza virus with particular emphasis on the M2 proton channel. Influmedix's founding scientist, Dr. William DeGrado of the University of Pennsylvania, is a key advisor to efforts at Influmedix and is the first scientist to have determined the high resolution crystal structure of the viral M2 protein (Nature, 2008, 451, 596-600), thus enabling structure-based drug design of agents that inhibit this channel and its drug resistant forms. The M2 protein is a selective proton channel essential for viral RNA to be released and taken up into the nucleus of the infected cell and a well validated drug target for influenza. First generation M2 inhibitors (amantadine and rimantadine) were effective for several decades until resistance developed in most influenza virus strains.
Resistance to amantadine and rimantadine arises from mutations in the M2 gene; despite the fact that the virus mutates at a great rate and a number of drug-resistant M2 mutants can be selected in the presence of amantadine in infected humans, animals, and cell culture, only a very limited number appear to be permissible in highly transmissible viruses and are fit to persist in the general population. As it is difficult to predict which M2 mutation will dominate in the next influenza A viruses outbreak, novel antivirals targeting all strains of flu viruses are in emerging demand, and combined therapies with more than two antiviral drugs in case of severe flu pandemic.
Influmedix utilizes structure-based design approaches that rely on detailed structural knowledge of the M2 proton channel and its drug binding site to design novel M2 blockers. Using these approaches, Influmedix has identified lead compounds that are very potent in vitro inhibitors of key M2 drug-resistant strains of flu, and advanced them to preclinical in vivo studies. Influmedix's goal is to have a pipeline of compounds that are effective against all possible drug-resistant M2 variants that may arise.