The specific aim of this program is to design and synthesize improved active site directed inhibitors of cruzain, the major cysteine protease of Trypanosoma cruzi. Peptide mimetics and non-peptidic inhibitors will be designed with the aid of insights deriving from: (i) The X-ray structure recently solved by Fletterick and McGrath, which has a covalently bound Z-Phe-Ala-FMK inhibitor at the active site: (ii) Knowledge of the structural requirements of the dipeptide fluoromethyl ketones (FMK) that McKerrow and coworkers have demonstrated to be potent, irreversible inhibitors of purified cruzain, and also to be active in vivo against Trypanosoma cruzi; and, (iii) Structural information deriving from the DOCK-generated, non- peptidic lead inhibitor structures deriving from the work of Cohen and Ring. In addition, a new class of cysteine protease inhibitors based on the E- 64 motif will be developed. Specifically, inhibitors incorporating epoxypropionyl ketone (EPK) substructures will be synthesized and evaluated by our parasitology and biochemistry collaborators, McKerrow and Engel, at UC San Francisco. Further modifications and optimization of the initial EPK inhibitors will be performed if promising activity as cruzain inhibitors is observed. The focus of these efforts is to identify modifications of the lead inhibitor structures already identified (see Background and Significance Section) so as to enhance their use in vivo. Factors such as absorption from the oral route, eliminating functional groups that may contribute to toxic side reactions, and enhancing the activity and specificity of the inhibitors against the targeted protease, cruzain, will be evaluated in iterative cycles involving our synthesis group, the computer modeling group (Cohen), the protein structure groups (McGrath, Fletterick and Craik), and the parasitology and biochemistry components of this program (McKerrow and Engel). These combined efforts will lead to the design and synthesis of ever more specific and potent cruzain inhibitors.
| Lee, Gregory M; Balouch, Eaman; Goetz, David H et al. (2012) Mapping inhibitor binding modes on an active cysteine protease via nuclear magnetic resonance spectroscopy. Biochemistry 51:10087-98 |
| Doyle, Patricia S; Zhou, Yuan M; Hsieh, Ivy et al. (2011) The Trypanosoma cruzi protease cruzain mediates immune evasion. PLoS Pathog 7:e1002139 |
| Boyom, Fabrice Fekam; Fokou, Patrick Valere Tsouh; Yamthe, Lauve Rachel Tchokouaha et al. (2011) Potent antiplasmodial extracts from Cameroonian Annonaceae. J Ethnopharmacol 134:717-24 |
| Swenerton, Ryan K; Zhang, Shuyi; Sajid, Mohammed et al. (2011) The oligopeptidase B of Leishmania regulates parasite enolase and immune evasion. J Biol Chem 286:429-40 |
| Robertson, Stephanie A; Renslo, Adam R (2011) Drug discovery for neglected tropical diseases at the Sandler Center. Future Med Chem 3:1279-88 |
| Huang, Niu; Jacobson, Matthew P (2010) Binding-site assessment by virtual fragment screening. PLoS One 5:e10109 |
| Chen, Yen Ting; Brinen, Linda S; Kerr, Iain D et al. (2010) In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi. PLoS Negl Trop Dis 4: |
| Chen, Chiung-Kuang; Leung, Siegfried S F; Guilbert, Christophe et al. (2010) Structural characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei bound to the antifungal drugs posaconazole and fluconazole. PLoS Negl Trop Dis 4:e651 |
| Brak, Katrien; Kerr, Iain D; Barrett, Kimberly T et al. (2010) Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy. J Med Chem 53:1763-73 |
| Guiguemde, W Armand; Shelat, Anang A; Bouck, David et al. (2010) Chemical genetics of Plasmodium falciparum. Nature 465:311-5 |
Showing the most recent 10 out of 126 publications
