Novel beta lactams as inhibitors of ebola virus infections

DESCRIPTION provided by applicant Ebola virus EBOV is a member of the filovirus family that causes severe viral hemorrhagic fever VHF Although infrequent epidemics of EBOV can cause high mortality rates of up to the subsequent medical and social upheaval can be widespread and severe as seen in the recent outbreak in Western Africa which has already caused more than fatalities in a region with insubstantial medical services Although some success using monoclonal and polyclonal antibodies has been reported these expensive treatments are not widely available to poorer regions of Africa without substantial assistance from America and Europe additionally it would be beneficial to have the ability to stockpile treatments in case of future outbreaks or bioterrorism This option is not easily achieved with antibody therapies A pressing need for small molecule therapeutics is thus quite evident The experimental drugs brincidofovir favipiravir and BCX have shown promise in vitro but no clinical trials have proven their effectiveness in vivo To address this critical unmet medical need new small molecule therapeutics prophylactics are necessary to avert the risk of future epidemics Using a pseudotype virus that mimics the viral entry process of EBOV we have identified a novel set of small molecule EBOV entry inhibitors that has been validated in assays of infectious EBOV in vitro Based on a beta lactam central core these compounds are readily modified are drug like and represent an excellent starting point for medicinal chemistry optimization By synthesizing new analogs of the hit compound MBX we will generate structure activity relationships to better understand the chemical features that lead to potent anti EBOV activity and low cytotoxicity and ultimately produce potent selective inhibitors of infectious EBOV that display drug like characteristics The current proposal will use medicinal chemistry to optimize MBX using three aims We will synthesize novel analogs of MBX and assay the antiviral activity in a pseudotype assay of EBOV infection We will validate the results of the pseudotype assay using infectious EBOV under BSL conditions We will measure in vitro ADME predictors to improve the overall drug likeness of the scaffold Using an iterative process of compound design synthesis and biological assay we will synthesize optimized compounds that are potent selective and have drug like properties suitable for further development as therapeutics and or prophylactics for EBOV infection PUBLIC HEALTH RELEVANCE This proposal is designed to optimize a series of compounds based on a beta lactam core for use as inhibitors of Ebola virus infection The compounds are an excellent starting point for medicinal chemistry because they are small drug like and readily modified By synthesizing new compounds testing their biological activity against an EBOV pseudotype virus rVSV EBOV and infectious EBOV measuring predictive in vitro ADME predictors and using that information to further improve the design and synthesis of subsequent inhibitors we will synthesize novel small molecule EBOV inhibitors that will have a high probability of succeeding in preclinical development en route to an effective therapeutic for EBOV infections