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The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease.
| Title | The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease. |
| Publication Type | Journal Article |
| Year of Publication | 2005 |
| Authors | Hucke, O, Gelb, MH, Verlinde, CLMJ, Buckner, FS |
| Journal | J Med Chem |
| Volume | 48 |
| Issue | 17 |
| Pagination | 5415-8 |
| Date Published | 2005 Aug 25 |
| ISSN | 0022-2623 |
| Keywords | Alkyl and Aryl Transferases, Animals, Binding Sites, Chagas Disease, Cytochrome P-450 Enzyme System, Humans, Lanosterol, Models, Molecular, Oxidoreductases, Protein Binding, Quinolones, Sterol 14-Demethylase, Structure-Activity Relationship, Trypanocidal Agents, Trypanosoma cruzi |
| Abstract | Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED(50) = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of Tipifarnib, providing a basis for the design of derivatives with selectivity for TcCYP51 over human PFT. |
| DOI | 10.1021/jm050441z |
| Alternate Journal | J. Med. Chem. |
| PubMed ID | 16107140 |
