3tik

Sterol 14-alpha demethylase (CYP51) from Trypanosoma brucei in complex with the tipifarnib derivative 6-((4-chlorophenyl)(methoxy)(1-methyl-1H-imidazol-5-yl)methyl)-4-(2,6-difluorophenyl)-1-methylquinolin-2(1H)-one

spinqualitylabelsall models 3tik, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3tik is a 4 chain structure with sequence from Trypanosoma (trypanozoon) brucei. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, JKF Related: 3g1q Gene: CYP51, Tb11.02.4080 (Trypanosoma (Trypanozoon) brucei) Activity: Sterol 14-demethylase, with EC number 1.14.13.70 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Chagas disease caused by the protozoan pathogen Trypanosoma cruzi remains a challenging infection due to the unavailability of safe and efficacious drugs. Inhibitors of the trypanosome sterol 14alpha-demethylase enzyme (CYP51), including azole antifungal drugs, are promising candidates for development as anti-Chagas drugs. Posaconazole is under clinical investigation for Chagas disease although the high cost of this drug may limit its widespread use. We have previously reported that the human protein farnesyltransferase (PFT) inhibitor, tipifarnib, has potent anti-T. cruzi activity by inhibiting the CYP51 enzyme. Furthermore, we have developed analogs that minimize the PFT inhibitory activity and enhance the CYP51 inhibition. In this paper, we describe the efficacy of the lead tipifarnib analog compared to posaconazole in a murine model of T. cruzi infection. The plasma exposure profiles for each compound following a single oral dose in mice and estimated exposure parameters after repeated twice-daily dosing for 20 days are also presented. The lead tipifarnib analog had potent suppressive activity on parasitemia in mice, but was unsuccessful at curing mice, whereas posaconazole as well as benznidazole cured 3 of 5 and 4 of 6 mice, respectively. The efficacy results are consistent with posaconazole having substantially higher predicted exposure than the tipifarnib analog after repeat twice daily administration. Further changes to the tipifarnib analogs to reduce plasma clearance are therefore likely to be important. A crystal structure of a trypanosomal CYP51 bound to a tipifarnib analog is reported herein, and provides new insights to guide structure-based drug design for further optimized compounds. Pharmacological Characterization, Structural studies, and In Vivo Activity of Anti-Chagas Disease Lead Compounds Derived from Tipifarnib.,Buckner FS, Bahia MT, Suryadevara PK, White KL, Shackleford DM, Chennamaneni NK, Hulverson MA, Laydbak JU, Chatelain E, Scandale I, Verlinde CL, Charman SA, Lepesheva GI, Gelb MH Antimicrob Agents Chemother. 2012 Jul 9. PMID:22777048 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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