A program for the development of new agents to treat T. Cruzi, the parasite responsible for Chagas' Disease, is presented. Cruzain, a cysteine protease is identified as a target for a structure based drug discovery program. Models of the three-dimensional structure of cruzain built by homology to other cysteine proteases of known structure and the recently determined x-ray structure of cruzain will be used as a template for the in compuo screening of the fine chemicals directory, a data base of about 70,000 purchaseable small molecules. Compounds selected in this computer based screen will be characterized experimentally. We expect that 2-10% of the computer selected inhibitors will be active experimentally against the enzyme at concentrations less than 100 microM. Already, we have identified cruzain inhibitors active at 2-4 microM concentrations. Free energy perturbation calculations will be used to help the synthetic chemists develop more active compounds. Some will be based on the non-peptidic leads derived from the computer data base searches, while others will be analogs of the nanomolar mechanistic inhibitor Z-Phe-Arg-FMK (Z= carbobenzoxy, FMK = fluoromethyl ketone) that have been altered to eliminate peptide character. A close interaction between molecular biology, structural biology, synthetic chemistry and computational chemistry will be used to exploit a structure based drug design cycle.
| 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 |
| Na, Byoung-Kuk; Bae, Young-An; Zo, Young-Gun et al. (2010) Biochemical properties of a novel cysteine protease of Plasmodium vivax, vivapain-4. PLoS Negl Trop Dis 4:e849 |
| Sun, Lingzhi; Shah, Falgun; Helal, Mohamed A et al. (2010) Design, synthesis, and development of novel guaianolide-endoperoxides as potential antimalarial agents. J Med Chem 53:7864-8 |
| Loser, Reik; Gut, Jiri; Rosenthal, Philip J et al. (2010) Antimalarial activity of azadipeptide nitriles. Bioorg Med Chem Lett 20:252-5 |
| Kerr, Iain D; Wu, Peng; Marion-Tsukamaki, Rachael et al. (2010) Crystal Structures of TbCatB and rhodesain, potential chemotherapeutic targets and major cysteine proteases of Trypanosoma brucei. PLoS Negl Trop Dis 4:e701 |
| Huang, Niu; Jacobson, Matthew P (2010) Binding-site assessment by virtual fragment screening. PLoS One 5:e10109 |
Showing the most recent 10 out of 126 publications
