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.

التفاصيل البيبلوغرافية
العنوان:	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.
المؤلفون:	Guedes-da-Silva FH; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Batista DG; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Da Silva CF; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., De Araújo JS; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Pavão BP; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Simões-Silva MR; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Batista MM; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Demarque KC; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Moreira OC; Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Britto C; Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil., Lepesheva GI; Department of Biochemistry, School of Medicine, Institute for Global Health, Vanderbilt University, Nashville, Tennessee, USA., Soeiro MN; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil soeiro@ioc.fiocruz.br.
المصدر:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2017 Mar 24; Vol. 61 (4). Date of Electronic Publication: 2017 Mar 24 (Print Publication: 2017).
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: Washington, American Society for Microbiology
مواضيع طبية MeSH:	14-alpha Demethylase Inhibitors/pharmacology , Chagas Disease/drug therapy , Cytochrome P-450 Enzyme System/chemistry , Imidazoles/pharmacology , Oxadiazoles/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/*drug effects, 14-alpha Demethylase Inhibitors/chemistry ; Animals ; Chagas Disease/immunology ; Chagas Disease/parasitology ; Cyclophosphamide/adverse effects ; Cytochrome P-450 Enzyme System/genetics ; Cytochrome P-450 Enzyme System/metabolism ; Disease Models, Animal ; Drug Administration Schedule ; Female ; Gene Expression ; Humans ; Imidazoles/chemistry ; Immunosuppressive Agents/adverse effects ; Male ; Mice ; Models, Molecular ; Nitroimidazoles/pharmacology ; Oxadiazoles/chemistry ; Parasite Load ; Recurrence ; Survival Analysis ; Trypanocidal Agents/chemistry ; Trypanosoma cruzi/enzymology ; Trypanosoma cruzi/genetics ; Trypanosoma cruzi/growth & development
مستخلص:	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 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 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. (Copyright © 2017 American Society for Microbiology.)
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معلومات مُعتمدة:	R01 GM067871 United States GM NIGMS NIH HHS
فهرسة مساهمة:	Keywords: Chagas disease; Trypanosoma cruzi; VFV; VNI; chemotherapy; inhibitors; sterol 14α-demethylase
المشرفين على المادة:	0 (14-alpha Demethylase Inhibitors) 0 (CYP51 protein, Trypanosoma cruzi) 0 (Imidazoles) 0 (Immunosuppressive Agents) 0 (Nitroimidazoles) 0 (Oxadiazoles) 0 (Trypanocidal Agents) 0 (VNI compound) 8N3DW7272P (Cyclophosphamide) 9035-51-2 (Cytochrome P-450 Enzyme System) YC42NRJ1ZD (benzonidazole)
تواريخ الأحداث:	Date Created: 20170208 Date Completed: 20171010 Latest Revision: 20190322
رمز التحديث:	20221213
مُعرف محوري في PubMed:	PMC5365685
DOI:	10.1128/AAC.02098-16
PMID:	28167559
قاعدة البيانات:	MEDLINE

الوصف
تدمد:	1098-6596
DOI:	10.1128/AAC.02098-16