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.
Chagas disease is a life-threatening infection caused by a variety of genetically diverse strains of the protozoan parasiteTrypanosoma cruziThe 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 protozoon-specific CYP51 inhibitors, VNI and its CYP51 structure-based derivative VFV, in the murine models of infection caused by the Y strain ofT. cruziThe 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 otherT. cruzistrains and in combination with other drugs.
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
F H
FH
Guedes-da-Silva
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
D G J
DG
Batista
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
C F
CF
Da Silva
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
J S
JS
De Araújo
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
B P
BP
Pavão
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
M R
MR
Simões-Silva
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
M M
MM
Batista
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
K C
KC
Demarque
Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
O C
OC
Moreira
Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
C
C
Britto
Department of Biochemistry, School of Medicine, Institute for Global Health, Vanderbilt University, Nashville, Tennessee, USA.
G I
GI
Lepesheva
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil soeiro@ioc.fiocruz.br.
M N C
MN
Soeiro
D058888:14-alpha Demethylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000276:immunology / Q000469:parasitology; D003520:Cyclophosphamide / Q000009:adverse effects; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009593:Nitroimidazoles / Q000494:pharmacology; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D059208:Parasite Load; D012008:Recurrence; D016019:Survival Analysis; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development
D058888:14-alpha Demethylase Inhibitors; C509352:CYP51 protein, Trypanosoma cruzi; D007093:Imidazoles; D007166:Immunosuppressive Agents; D009593:Nitroimidazoles; D010069:Oxadiazoles; D014344:Trypanocidal Agents; C578921:VNI compound; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; C009999:benzonidazole
Chagas disease; Trypanosoma cruzi; VFV; VNI; chemotherapy; inhibitors; sterol 14α-demethylase