A Computer Modeling Approach

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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 20% within 3 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 530,000 annual deaths among HIV positive patients compared with 350,000 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 (CI'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 1. Generate closely related analogs of the 6 early lead compounds from Phase I. Aim 2. Characterize compounds in vitro for advancement. Iterate library as required. Aim 3. Characterize compounds in vivo for pharmacokinetics and efficacy.