The overall aim of this research program is to develop novel, potent and highly selective inhibitors of cruzain, the major cysteine protease of Trypanosoma cruzi; falcipain-2 and -3, the major cysteine proteases of the Plasmodium falciparum trophozoite; rhodesain from Trypanosoma brucei rhodesiense; and the cathepsin B-like (Lmaicatb) and L-like cysteine proteases from Leishmania major. Efforts will be made to develop a single cysteine protease inhibitor that is effective against all of the targeted parasites.
Specific aims for the next grant period include: (1) Optimization of the vinyl sulfonyl inhibitor P' substituent. (2) Development of a solid-phase synthesis of vinyl sulfonyl inhibitors. (3) Continued development and optimization of E-64 analogs. (4) Development of conformationally constrained cysteine protease inhibitors. (5) Development of heterocycle-based peptidometics as cysteine protease inhibitors. (6) Determination of enzyme-bound inhibitor conformations and active site structures via transferred Nuclear Overhauser Effect (TRNOE) and residual dipolar coupling studies. (7) NMR screening of new inhibitor scaffolds. All enzymatic and biological evaluation of the inhibitors will be performed at UCSF (McKerrow for cruzain, rhodesain and the leishmania enzymes; Rosenthal for falcipains-2 and -3). To the extent possible, the best inhibitors will be characterized by X-ray analysis of the inactivated enzyme. Inhibitor complexes of the targeted proteases that have not yielded to crystallographic analysis will be characterized by NMR methods.
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| 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 |
| Doyle, Patricia S; Zhou, Yuan M; Hsieh, Ivy et al. (2011) The Trypanosoma cruzi protease cruzain mediates immune evasion. PLoS Pathog 7:e1002139 |
| 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 |
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