Expanding the binding envelope of CYP51 inhibitors targeting Trypanosoma cruzi with 4-aminopyridyl-based sulfonamide derivatives.
Chagas disease is a chronic infection caused by the protozoan parasite Trypanosoma cruzi, manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Therapeutic options to prevent or treat Chagas disease are limited. CYP51, the enzyme key to the biosynthesis of eukaryotic membrane sterols, is a validated drug target in both fungi and T. cruzi. Sulfonamide derivatives of 4-aminopyridyl-based inhibitors of T. cruzi CYP51 (TcCYP51), including the sub-nanomolar compound 3, have molecular structures distinct from other validated CYP51 inhibitors. They augment the biologically relevant chemical space of molecules targeting TcCYP51. In a 2.08 Å X-ray structure, TcCYP51 is in a conformation that has been influenced by compound 3 and is distinct from the previously characterized ground-state conformation of CYP51 drug-target complexes. That the binding site was modulated in response to an incoming inhibitor for the first time characterizes TcCYP51 as a flexible target rather than a rigid template.
Department of Pathology, Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, 1700 4th Street, San Francisco, CA 94158 (USA).
Debora F
DF
Vieira
Jun Yong
JY
Choi
William R
WR
Roush
Larissa M
LM
Podust
D058888:14-alpha Demethylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D032446:Myoblasts / Q000187:drug effects / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D058886:Sterol 14-Demethylase / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
D058888:14-alpha Demethylase Inhibitors; D013449:Sulfonamides; D014344:Trypanocidal Agents; D058886:Sterol 14-Demethylase
CYP51; Chagas disease; drug design; inhibitors; protein structures