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The opportunistic pathogen Candida albicans is a leading cause of fungal disease in humans, resulting in both superficial and life-threatening infections.  C. albicans can grow in different cell shapes, including round yeast-like cells and highly filamentous cells, called true hyphae and pseudohyphae.  Yeast and filamentous cells have been observed at the sites of Candida infection, and there is compelling evidence that morphogenesis, the transition between yeast and filamentous growth forms, is essential for virulence.  Thus, small molecules that inhibit morphogenesis may form the basis for a novel approach to controlling fungal infections.  We have recently shown that a small organic molecule called BH3I-1 inhibits morphogenesis in C. albicans (1).  BH3I-1 was originally identified as an inhibitor of the human Bcl-XL protein, an anti-apoptotic member of the Bcl-2 family of proteins.  Bcl-2 family proteins are not found in fungi, thus BH3I-1 inhibits a different, but unknown, protein in C. albicans.  BH3I-1 itself is not likely to be a good candidate for an anti-fungal drug, as it can induce apoptosis in human cells through its ability to bind to and inhibit Bcl-XL.  However, since BH3I-1 targets different proteins in humans and fungi, it is possible that there are derivatives of BH3I-1 that still inhibit morphogenesis, but no longer bind to Bcl-XL.  A molecule with the foregoing properties may be a good starting point for developing a novel anti-fungal therapeutic that is minimally toxic to human cells.

Specific Aim

Identify derivatives of BH3I-1 that have reduced affinity for Bcl-XL yet retain the ability to inhibit C. albicans morphogenesis.

Rationale.  BH3I-1 itself is not likely to be a good candidate for an anti-fungal drug, as it can bind to Bcl-XL and induce apoptosis in human cells.  Bioinformatic analyses indicate that fungi do not encode Bcl-2 family proteins. Thus, BH3I-1 targets a protein different from Bcl-XL in fungi.  Even though the BH3I-1 binding site of Bcl-XL and the unknown fungal target must share some structural similarity, they apparently do not share amino acid sequence similarity, since there are no obvious homologues for Bcl-XL in fungi. Thus, it may be possible to find BH3I-1 derivatives that inhibit morphogenesis, but do not bind, or bind with lower affinity, to Bcl-XL. To search for derivatives with these properties, we will use a three-step approach involving (a) computational methods and 3-dimensional structural models to “virtually screen” approximately 2300 known BH3I-1 derivatives from the ChemBridge Hit2Lead collection for binding affinity to Bcl-XL, (b) testing candidate molecules from the virtual screen with in vivo and in vitro Bcl-XL binding assays, and (c) testing lead candidates from the Bcl-XL binding assays for inhibition of morphogenesis in C. albicans using our standard assay.  

Primary Contact

David Butler