Protease resistant D peptide Inhibitors of Ebola Virus Entry

DESCRIPTION provided by applicant Ebola virus causes highly lethal hemorrhagic fever in humans and non human primates Since the first outbreak in there have been over natural human outbreaks with an average mortality rate near There are no approved agents to prevent or treat Ebola infection Due to ease of dissemination high lethality and ability to cause widespread panic the CDC defines Ebola as a Category A bioterror agent their category of highest concern There is great need for an effective Ebola preventative and or treatment to combat both natural outbreaks and potential bioterror attacks Using an innovative mirror image design strategy Navigen has identified a novel D peptide drug lead to combat Ebola D peptides the mirror images of natural L peptides cannot be digested by proteases and therefore have the potential for long in vivo half lives and reduced immunogenicity As peptides they can readily disrupt andquot undruggableandquot large protein protein interfaces with high potency and specificity a rare trait for small molecule drugs Navigenandapos s drug discovery platform employs an enantiomeric screening technology mirror image phage display coupled with protein design to identify and then affinity mature D peptides that block viruses as they attempt to enter cells This platform technology has been successfully validated by Navigenandapos s optimized anti HIV drug currently in advanced preclinical development which binds to a highly conserved region on the HIV envelope protein and blocks entry in all major circulating HIV strains Ebola has a similarly conserved target on its surface protein GP Navigenandapos s anti Ebola drug lead binds to this conserved region and specifically inhibits pseudotyped Ebola entry into target cells with nanomolar potency In this three year SBIR grant Navigen proposes to affinity mature our lead candidate through innovative phage display techniques coupled with structure guided peptide design demonstrate efficacy against multiple Ebola strains in tissue culture perform preclinical pharmacokinetic PK studies and basic toxicology to support animal efficacy experiments and demonstrate efficacy in gatekeeper mouse and gold standard non human primate models of Ebola infection Upon completion of the proposed studies Navigen will be well positioned to execute studies that will lead to new drug approval via the Animal Rule PUBLIC HEALTH RELEVANCE Ebola virus causes a highly lethal hemorrhagic fever for which there are no approved therapeutics or vaccines More than natural Ebola virus outbreaks have occurred with four since the summer of and the virus poses a serious risk as a potential bioterror agent Category A CDC Navigen is developing a novel broad spectrum inhibitor of Ebola virus infection to help protect and or treat individuals during natural outbreak or a bioterror attack