ELONGATION FACTOR-3--A TARGET FOR ANTICRYPTOCOCCAL DRUGS

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The protein synthesis factor EF-3 is apparently unique to fungi, with no analogous factor present in prokaryotes, plants or animals. Therefore, EF-3 provides a unique target for the development of anticryptococcal agents and perhaps broad spectrum antifungal drugs which would be important in treating a range of other opportunistic infections in AIDS patients. EF-3 plays a complex biochemical role in its interaction with ribosomes, aminoacyl tRNA, trinucleotides and other elongation factors, making the interface between EF-3 and the ribosome a suitable target for a modeled inhibitor. We propose to define this interface with molecular genetic and biochemical analyses with the following specific aims: 1. To demonstrate that EF-3 is structurally and functionally conserved in fungi and thus a suitable target for a broad spectrum antifungal. 2. Identify the region of EF-3 which interacts with the ribosome, the residues involved and the nature of their interaction. 3. Identify the components of the ribosome which interact with EF-3 and the nature of their binding interface. Our long-range goals include structure-function studies of the EF-3 protein, and by way of collaboration, a 3-dimensional analysis of the binding sites. These studies should provide the information necessary to design cryptococcal-specific and fungal-specific antimicrobials with little or no toxic side effects.