DEVELOPMENT OF DRUGS THAT TARGET THE M2 PROTON CHANNEL FROM INFLUENZA A VIRUS

DESCRIPTION provided by applicant We have the discovered the first small molecule probes and drug candidates that effectively inhibit the most prevalent S N drug resistant mutant of the M proton channel of influenza the target of the marketed anti flu drugs amantadine and rimantadine We here propose to exploit our extensive structural biology work in this area to design new related analogs to increase potency for both the most prevalent mutants and wild type M and to understand and improve drug like properties to eventually discover new treatments for seasonal influenza infections Besides the yearly epidemic outbreaks influenza viruses are even more threatening pathogens due to their potency to cause pandemics as occurred in by the emergence and worldwide spread of the H N viruses Available prophylactic vaccines are not completely effective against emerging flu strains thus effective anti viral therapy is not an adjunct but an essential component of our options in the fight against influenza Two classes of drugs are currently approved as antiviral agents the M proton channel inhibitors Symmetrel amantadine and Flumadine rimantadine and the neuraminidase inhibitors Tamiflu oseltamivir and Relenza zanamivir While these drugs are effective in reducing symptomatology from influenza increasing resistance has severely limited their effectiveness Resistance to this class of drugs is associated with naturally occurring point mutations in the M channel pore comprised of a single helical strand through the virus outer coat and four of the M proteins taken together form a functional proton channel The effect of a single mutation is amplified four fold because it is present in all four of the helices that for the pore The S N mutant is the most prevalent and significant amantadine resistant mutation It is present in almost all of the currently circulating influenza strains as well as in the avian nd pandemic H N strains As a result there is an urgent need to develop second generation novel M inhibitors targeting all clinically relevant mutants of M and particularly the most prevalent S N mutant Current efforts have already identified several series of novel and potent in vitro compounds against S N as well as other clinically significant M variants such as V A Our first aim is to optimize the in vitro affinities and drug like properties of the existng series of M S N inhibitors using iterative medicinal chemistry We are uniquely situated to do this based upon our understanding as to the D structure of the pore The second aim is to optimize the in vitro ADME properties of top representative members of different series for in vivo probe and drug like suitability In Phase II we will advance the most promising lead candidates identified in Phase I through pharmacokinetic profiling additional ADME and off target safety studies and animal efficacy and toxicity tests with the ultimate goal of identifying one or more development candidates The long term goal of the program is to complete all studies necessary for filing an Investigational New Drug IND application PUBLIC HEALTH RELEVANCE Seasonal influenza infections as well as the emergence of life threatening strains of influenza are a major worldwide health concern Every year influenza epidemics cause numerous deaths and millions of hospitalizations We are using modern methods of structural biology and medicinal chemistry to discover new small molecule drug candidates that will inhibit not only the influenza wild type M proton channel but also the most prevalent S N and other mutants which are particularly drug resistant to current therapy