Inhibition of Protein Prenylation: a Novel Approach in Antifungal Therapy

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2011

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Tseng, Quincy

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Beese, Lorena S

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Abstract

Many proteins that are required for eukaryotic cell growth, differentiation, and cellular signaling pathways, including the Ras superfamily of GTP-binding proteins, go through prenylation, a post-translational modification of isoprenoid lipid attachment. Since prenylation of mutant Ras proteins is necessary for their oncogenic effects, protein prenyltransferases have been targets for cancer therapeutics. These enzymes have also been identified and shown to be essential in several fungal and protozoan organisms that exist as opportunistic human pathogens. Some of the mammalian protein prenyltransferase inhibitors, used as chemotherapeutic agents in clinical trials, exhibit antifungal properties and have the potential to be adapted for antifungal therapies. The prenylation pathway is therefore an attractive target for treating fungal infections.

The focus of this project is on the fungal organism Aspergillus fumigatus, a major opportunistic human pathogen of invasive aspergillosis that is becoming more common among transplant recipients and cancer and AIDS patients. To approach inhibitor design for A. fumigatus protein prenyltransferases, I have described a 1.5 Å X-ray crystal structure of the A. fumigatus protein farnesyltransferase (FTase) in complex with farnesyl diphosphate and its active site features that include isoprenoid and peptide binding conformations, zinc coordination, and product exit groove. Additionally, an in vitro fluorescence-based activity assay was used to partially characterize the peptide substrate specificity of the enzyme. I have also obtained crystal structures of the A. fumigatus FTase in complex with two ethylenediamine-scaffold compounds and evaluated the binding mode and selectivity of the compounds relative to that in mammalian FTase. Given the limited effectiveness of current antifungal therapies, the work presented here may lead to the design of new fungal inhibitors with improved selectivity.

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Tseng, Quincy (2011). Inhibition of Protein Prenylation: a Novel Approach in Antifungal Therapy. Master's thesis, Duke University. Retrieved from https://hdl.handle.net/10161/5061.

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