Research Project
8732202
DESCRIPTION (provided by applicant): Cryptococcal meningitis (CM) is the AIDS-defining illness for 60-70% of HIV positive individuals with an estimated worldwide occurrence of 1 million cases annually. CM is invariably fatal if left untreated, In sub-Saharan Africa alone, CM causes over 500,000 annual deaths among HIV positive patients compared with 350,000 annual deaths for tuberculosis in the general population. A particular challenge with the discovery of antifungal drugs is toxicity due to the similarities between the fungal and human eukaryotic genomes. The cyclic peptide, Aureobasidin A (AbA), patented in 1992 by Takara Shuzo, is a potent compound with strong, fungicidal activity vs. Cryptococcus neoformans comparable to Amphotericin B. AbA is a specific inhibitor of the inositol phosphorylceramide 1 synthase (IPC1 synthase) catalyzed addition of inositolphosphate to phytoceramide, a step in the sphingolipid pathway in fungi but absent in mammals. Consistent with the lack of IPC1 synthase in mammals, AbA demonstrated excellent tolerability in a Phase I clinical trial performed by Eli Lilly in the mid 1990's and has demonstrated efficacy in animal models of CM. Expression of IPC1 synthase is essential for virulence in C. neoformans, as well as other pathogenic fungi including Candida albicans and Aspergillus fumigatus. The challenge with employing AbA itself as a therapeutic is the low bioavailability of the compound. Moreover, there has been a lack of tractable chemical methods to generate AbA analogues that can be tested for ease of formulation and improved oral availability. Recently, our collaborators at Aureogen have developed robust, 2-3 step chemistries to produce analogues of AbA. This is remarkable improvement over the prior 21 step chemistries employed to create AbA analogues for testing. One analogue tested, AUGC-15, exhibited > 8-fold improved oral availability vs. AbA while maintaining high potency and robust fungicidal activity vs. drug susceptible and drug resistant strains of C. neoformans. Encouraged by these preliminary data, we hope to develop an orally available, fungicidal therapeutic to improve treatment outcomes for CM patients. Aim 1. Employ initial library screening results and SAR to design and synthesize an initial small library of 20 IPC1 synthase inhibitors. Aim 2. Screen and select compounds for antifungal activity against C. neoformans and C. gattii for low cytoxicity vs. HepG2 cells and improved pk. Aim 3. Iterate library as needed based on initial SAR as needed to achieve more extensive pk/pd milestones and retest 20 additional IPC1 synthase inhibitors.
