Abstract
Trypanosoma cruzi causes Chagas disease (American trypanosomiasis), which threatens the lives of millions of people and remains incurable in its chronic stage. The antifungal drug posaconazole that blocks sterol biosynthesis in the parasite is the only compound entering clinical trials for the chronic form of this infection. Crystal structures of the drug target enzyme, Trypanosoma cruzi sterol 14alpha-demethylase (CYP51), complexed with posaconazole, another antifungal agent fluconazole and an experimental inhibitor, (R)-4'-chloro-N-(1-(2,4-dichlorophenyl)-2-(1H-imid-azol-1-yl)ethyl)biphenyl-4-carboxamide (VNF), allow prediction of important chemical features that enhance the drug potencies. Combined with comparative analysis of inhibitor binding parameters, influence on the catalytic activity of the trypanosomal enzyme and its human counterpart, and their cellular effects at different stages of the Trypanosoma cruzi life cycle, the structural data provide a molecular background to CYP51 inhibition and azole resistance and enlighten the path for directed design of new, more potent and selective drugs to develop an efficient treatment for Chagas disease.
Highlights
Chagas disease is a deadly protozoan infection endemic in Central and South America.2 With human migration and HIV co-infections, it is found in all other parts of the globe [2,3,4,5]
An estimated 16 to 18 million people are infected with Trypanosoma cruzi (TC), and ϳ50,000 people die each year [3]
Sterol 14␣-demethylase (14DM,3 CYP51 gene family), the membrane-bound cytochrome P450 catalyzing oxidative removal of the 14␣-methyl group from the sterol core, is a highly drug-targetable enzyme in sterol biosynthetic pathways [13]. 14DM is strongly inhibited by heterocyclic compounds with a basic atom that coordinates to the heme iron affecting substrate binding and catalysis. 14DM inhibitors are among the most efficient current antifungal drugs [14, 15]
Summary
Posaconazole is a highly potent broad spectrum antifungal drug, approved by the U.S Food and Drug Administration in 2006 as salvage therapy for invasive fungal infections in immunocompromised patients [15, 17, 24] The disadvantages of this drug include its cost and severe adverse side effects, especially gastrointestinal problems, because the drug is produced only in an orally available form. Despite the differences in the inhibitor structures, molecular volumes, and binding poses, they do not cause large scale conformational rearrangements in the enzyme, filling the available active site cavity without significantly changing its shape and topology This characterizes 14DM as possibly one of the most structurally rigid members of the cytochrome P450 superfamily [28] and provides an excellent basis for structure-directed design of new, highly potent and ideally pathogen-specific drugs. Low doses of VNF produce a steady antiparasitic effect over time, which distinguishes this inhibitory scaffold as a very promising lead for antitrypanosomal therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
