Human African Trypanosomiasis (HAT), endemic to some rural communities in sub-Saharan Africa, is caused by the protozoan Trypanosoma brucei. Over 50% of trypanosomes genes have no homologs in other eukaryotes. Many aspects of trypanosome signaling pathways are not understood. Current drugs are suboptimal, being toxic and difficult to administer. New drugs are needed to treat the disease which has been designated by the World Health Organization as a neglected tropical disease. We are interested in first, delineating trypanosome pathways that differ significantly from host systems so that they may become the focus of efforts to discover new lead drugs. Second, we are identifying small chemical probes that may used to study trypanosome cell biology, to complement RNA interference experiments: Since there is little homology of trypanosome proteins to those in well-studied systems (e.g. vertebrates or yeasts), homology-based strategies to characterize proteins in T. brucei frequently yields inconclusive results. A Discovery Chemical Biology protocol entails screening small drug-like molecules for a phenotypic change in the trypanosome. The small molecules are then used as chemical tools to identify their target proteins that can be used to discover genes encoding them. Genes for the target proteins are then knocked down in order to find out which of them are modulators of phenotypes conferred by the small molecule probes (Fig. 1). This Discovery Chemical Biology strategy has been applied to reveal novel regulatory genes for transferrin endocytosis, and basal body biogenesis. Along with these chemical and molecular cell biology studies, we have collaborations with the Pollastri and Swinney laboratories, as well as Cleveland BioLabs (see below) to (a) discover small molecule inhibitors of select trypanosome protein kinases by high throughput screening, and (b) optimize our chemical probes into leads for for anti-trypanosome drug discovery.
- Michael Pollastri (Northeastern University) – Medicinal Chemistry
- David Swinney (Institute of Rare and Neglected Diseases Drug Discovery) – High Throughput Screens.
- Andrei Purmal (Cleveland BioLabs, Inc.) – Pharmacokinetics, ADME, and Toxicity of Drug Leads
- George Zheng (University of Georgia) – Chemical Biology
Affiliations at UGA
- Behera R, Thomas SM, Mensa-Wilmot K. New chemical scaffolds for human african trypanosomiasis lead discovery from a screen of tyrosine kinase inhibitor drugs. Antimicrob Agents Chemother. 2014;58(4):2202-10.
- Patel G, Karver CE, Behera R, Guyett PJ, Sullenberger C, Edwards P, Roncal NE, Mensa-Wilmot K, Pollastri MP. Kinase scaffold repurposing for neglected disease drug discovery: discovery of an efficacious, lapatinib-derived lead compound for trypanosomiasis. J Med Chem. 2013 May 23;56(10):3820-32.
- Katiyar S, Kufareva I, Behera R, Thomas SM, Ogata Y, Pollastri M, Abagyan R, Mensa-Wilmot K. Lapatinib-binding protein kinases in the African trypanosome: identification of cellular targets for kinase-directed chemical scaffolds. PLoS One. 2013;8(2):e56150.
- Subramanya S, Armah DA, Mensa-Wilmot K. Trypanosoma brucei: reduction of GPI-phospholipase C protein during differentiation is dependent on replication of newly transformed cells. Exp Parasitol. 2010 Jul;125(3):222-9.
- Subramanya S, Mensa-Wilmot K. Diacylglycerol-stimulated endocytosis of transferrin in trypanosomatids is dependent on tyrosine kinase activity. PLoS One. 2010 Jan 1;5(1):e8538.
- Duffy J, Patham B, Mensa-Wilmot K. Discovery of functional motifs in h-regions of trypanosome signal sequences. Biochem J. 2010 Feb 9;426(2):135-45.
- Patham B, Duffy J, Lane A, Davis RC, Wipf P, Fewell SW, Brodsky JL, Mensa-Wilmot K. Post-translational import of protein into the endoplasmic reticulum of a trypanosome: an in vitro system for discovery of anti-trypanosomal chemical entities. Biochem J. 2009 Apr 15;419(2):507-17.
- Subramanya S, Hardin CF, Steverding D, Mensa-Wilmot K. Glycosylphosphatidylinositol-specific phospholipase C regulates transferrin endocytosis in the African trypanosome. Biochem J. 2009 Feb 1;417(3):685-94.
- Stanton JD, Mensa-Wilmot K. AUG-proximal nucleotides regulate protein synthesis in Leishmania tropica. Mol Microbiol. 2006 Aug;61(3):691-703. Epub 2006 Jun 20.
- Subramanya S, Mensa-Wilmot K. Regulated cleavage of intracellular glycosylphosphatidylinositol in a trypanosome. Peroxisome-to-endoplasmic reticulum translocation of a phospholipase C. FEBS J. 2006 May;273(10):2110-26.