A Computer Modeling Approach

DESCRIPTION Cryptococcal meningitis CM continues to be a significant cause of mortality among HIV positive individuals and a major worldwide health concern The estimated mortality rate for HIV infected acute CM patients is within months after infection in North America despite patient access to good health care resources In sub Saharan Africa alone the effects of CM are devastating an estimated annual deaths among HIV positive patients compared with annual deaths for tuberculosis in the general population CM symptoms include severe headaches nausea and vomiting related to increased intracranial pressure The first line therapeutic to treat CM is currently Amphotericin B AmB a fungicidal i v administere agent and is sometimes co administered with flucytosine AmB and alternative lipid formulations are administered intravenously and cause side effects including nephrotoxicity leukopenia and cardiac arrhythmia Although multiple factors contribute to the high mortality rates of CM the discovery of an orally available efficacious alternative to AmB would add an important treatment option to combat this devastating illness We propose exploiting fungal calcineurin an essential membrane stress response protein to create a new class of antifungals Through the work of our collaborator Joe Heitman and others it has been shown that targeting fungal calcineurin has great potential in treating cryptococcal disease both as monotherapy and in combination with other antifungals including fluconazole and AmB Calcineurin inhibitors CIandapos s exhibit superior in vitro potency compared with AmB against Cryptococcus neoformans In addition combining a fungal CI with a fungistatic triazole such as fluconazole or posaconazole results in a fungicidal combination which would likely reduce the time period required for maintenance therapy and help avoid the increased incidence of resistant cryptococcal strains The work proposed here will be a continuation of a Phase I project where we were able to demonstrate in vivo efficacy vs a drug resistant strain of C neoformans employing a novel fungal calcineurin inhibitor Aim Generate closely related analogs of the early lead compounds from Phase I Aim Characterize compounds in vitro for advancement Iterate library as required Aim Characterize compounds in vivo for pharmacokinetics and efficacy PUBLIC HEALTH RELEVANCE Cryptococcal meningitis CM continues to be a significant cause of mortality among HIV positive individuals and a major world wide health concern in developing regions including Africa and Southeast Asia where mortality rates reach There is a clear need for new cost effective therapeutics which will enable patient compliance with treatment regimens Amplyx proposes to create a new class of orally available antifungal drugs with fungicidal activity against Cryptococcus which will simplify and reduce the duration of treatment regimens and lower the mortality rates due to cryptococcosis