Dataset Information

Antitrypanosomal Activity of Sterol 14?-Demethylase (CYP51) Inhibitors VNI and VFV in the Swiss Mouse Models of Chagas Disease Induced by the Trypanosoma cruzi Y Strain.

ABSTRACT: Chagas disease is a life-threatening infection caused by a variety of genetically diverse strains of the protozoan parasite Trypanosoma cruzi The current treatment (benznidazole and nifurtimox) is unsatisfactory, and potential alternatives include inhibitors of sterol 14?-demethylase (CYP51), the cytochrome P450 enzyme essential for the biosynthesis of sterols in eukaryotes and the major target of clinical and agricultural antifungals. Here we performed a comparative investigation of two protozoon-specific CYP51 inhibitors, VNI and its CYP51 structure-based derivative VFV, in the murine models of infection caused by the Y strain of T. cruzi The effects of different treatment regimens and drug delivery vehicles were evaluated in animals of both genders, with benznidazole serving as the reference drug. Regardless of the treatment scheme or delivery vehicle, VFV was more potent in both genders, causing a >99.7% peak parasitemia reduction, while the VNI values varied from 91 to 100%. Treatments with VNI and VFV resulted in 100% animal survival and 0% natural relapse after the end of therapy, though, except for the 120-day treatment schemes with VFV, relapses after three cycles of immunosuppression were observed in each animal group, and quantitative PCR analysis revealed a very light parasite load in the blood samples (sometimes below or near the detection limit, which was 1.5 parasite equivalents/ml). Our studies support further investigations of this class of compounds, including their testing against other T. cruzi strains and in combination with other drugs.

SUBMITTER: Guedes-da-Silva FH

PROVIDER: S-EPMC5365685 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Antitrypanosomal Activity of Sterol 14α-Demethylase (CYP51) Inhibitors VNI and VFV in the Swiss Mouse Models of Chagas Disease Induced by the Trypanosoma cruzi Y Strain.

Guedes-da-Silva F H FH Batista D G J DG Da Silva C F CF De Araújo J S JS Pavão B P BP Simões-Silva M R MR Batista M M MM Demarque K C KC Moreira O C OC Britto C C Lepesheva G I GI Soeiro M N C MN

Antimicrobial agents and chemotherapy 20170324 4

Chagas disease is a life-threatening infection caused by a variety of genetically diverse strains of the protozoan parasite <i>Trypanosoma cruzi</i> The current treatment (benznidazole and nifurtimox) is unsatisfactory, and potential alternatives include inhibitors of sterol 14α-demethylase (CYP51), the cytochrome P450 enzyme essential for the biosynthesis of sterols in eukaryotes and the major target of clinical and agricultural antifungals. Here we performed a comparative investigation of two ...[more]

PMID: 28167559

Similar Datasets

Project description:Chagas disease, caused by the eukaryotic (protozoan) parasite Trypanosoma cruzi, is an alarming emerging global health problem with no clinical drugs available to treat the chronic stage. Azole inhibitors of sterol 14?-demethylase (CYP51) were proven effective against Chagas, and antifungal drugs posaconazole and ravuconazole have entered clinical trials in Spain, Bolivia, and Argentina. Here we present the x-ray structures of T. cruzi CYP51 in complexes with two alternative drug candidates, pyridine derivatives (S)-(4-chlorophenyl)-1-(4-(4-(trifluoromethyl)phenyl)-piperazin-1-yl)-2-(pyridin-3-yl)ethanone (UDO; Protein Data Bank code 3ZG2) and N-[4-(trifluoromethyl)phenyl]-N-[1-[5-(trifluoromethyl)-2-pyridyl]-4-piperi-dyl]pyridin-3-amine (UDD; Protein Data Bank code 3ZG3). These compounds have been developed by the Drugs for Neglected Diseases initiative (DNDi) and are highly promising antichagasic agents in both cellular and in vivo experiments. The binding parameters and inhibitory effects on sterol 14?-demethylase activity in reconstituted enzyme reactions confirmed UDO and UDD as potent and selective T. cruzi CYP51 inhibitors. Comparative analysis of the pyridine- and azole-bound CYP51 structures uncovered the features that make UDO and UDD T. cruzi CYP51-specific. The structures suggest that although a precise fit between the shape of the inhibitor molecules and T. cruzi CYP51 active site topology underlies their high inhibitory potency, a longer coordination bond between the catalytic heme iron and the pyridine nitrogen implies a weaker influence of pyridines on the iron reduction potential, which may be the basis for the observed selectivity of these compounds toward the target enzyme versus other cytochrome P450s, including human drug-metabolizing P450s. These findings may pave the way for the development of novel CYP51-targeted drugs with optimized metabolic properties that are very much needed for the treatment of human infections caused by eukaryotic microbial pathogens.

Dataset Information

Antitrypanosomal Activity of Sterol 14?-Demethylase (CYP51) Inhibitors VNI and VFV in the Swiss Mouse Models of Chagas Disease Induced by the Trypanosoma cruzi Y Strain.

Publications

Antitrypanosomal Activity of Sterol 14α-Demethylase (CYP51) Inhibitors VNI and VFV in the Swiss Mouse Models of Chagas Disease Induced by the Trypanosoma cruzi Y Strain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets