The protein farnesyltransferase inhibitor Tipifarnib as a new lead for the development of drugs against Chagas disease.
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.
Hucke
Oliver
O
Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA.
Gelb
Michael H
MH
Verlinde
Christophe L M J
CL
Buckner
Frederick S
FS
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D014355:Chagas Disease / Q000188:drug therapy; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D006801:Humans; D007810:Lanosterol / Q000737:chemistry; D008958:Models, Molecular; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011485:Protein Binding; D015363:Quinolones / Q000737:chemistry*; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000201:enzymology*
C548418:CYP51A1 protein, human; D065607:Cytochrome P-450 Enzyme Inhibitors; D015363:Quinolones; D014344:Trypanocidal Agents; D007810:Lanosterol; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C402769:tipifarnib