ArticleAntimicrobial agents and chemotherapy2013
In vitro and in vivo studies of the antiparasitic activity of sterol 14α-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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39 citing papers in PubMed, 77 citations in OpenAlex.
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- Antiplasmodial, Trypanocidal, and GenotoxicityPharmaceuticals (Basel, Switzerland) · 2023Article
- Exploring Synthetic Dihydrobenzofuran and Benzofuran Neolignans as Antiprotozoal Agents againstPharmaceutics · 2023Article
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- Perspectives for a new drug candidate for Chagas disease therapy.Memorias do Instituto Oswaldo Cruz · 2022Article
- Review on Experimental Treatment Strategies AgainstJournal of experimental pharmacology · 2021Review
- Chagas Disease: Perspectives on the Past and Present and Challenges in Drug Discovery.Molecules (Basel, Switzerland) · 2020Review
- Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistantParasitology · 2020Article
- Novel structural CYP51 mutation in Trypanosoma cruzi associated with multidrug resistance to CYP51 inhibitors and reduced infectivity.International journal for parasitology. Drugs and drug resistance · 2020Article
- Bisphosphonate-Based Molecules as Potential New Antiparasitic Drugs.Molecules (Basel, Switzerland) · 2020Review
- Current trends in the pharmacological management of Chagas disease.International journal for parasitology. Drugs and drug resistance · 2020Review
- Advances in preclinical approaches to Chagas disease drug discovery.Expert opinion on drug discovery · 2019Review
- Successful Aspects of the Coadministration of Sterol 14α-Demethylase Inhibitor VFV and Benznidazole in Experimental Mouse Models of Chagas Disease Caused by the Drug-Resistant Strain of Trypanosoma cruzi.ACS infectious diseases · 2019Article
- Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae.Journal of medicinal chemistry · 2018Article
- Experimental models in Chagas disease: a review of the methodologies applied for screening compounds against Trypanosoma cruzi.Parasitology research · 2018Review
- Repurposing Strategy of Atorvastatin against Trypanosoma cruzi:Antimicrobial agents and chemotherapy · 2018Article
- Outcome of E1224-Benznidazole Combination Treatment for Infection with a Multidrug-Resistant Trypanosoma cruzi Strain in Mice.Antimicrobial agents and chemotherapy · 2018Article
- Impact of autologous whole blood administration upon experimental mouse models of acuteThe journal of venomous animals and toxins including tropical diseases · 2018Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
Chagas disease affects more than 10 million people worldwide, and yet, as it has historically been known as a disease of the poor, it remains highly neglected. Two currently available drugs exhibit severe toxicity and low effectiveness, especially in the chronic phase, while new drug discovery has been halted for years as a result of a lack of interest from pharmaceutical companies. Although attempts to repurpose the antifungal drugs posaconazole and ravuconazole (inhibitors of fungal sterol 14α-demethylase [CYP51]) are finally in progress, development of cheaper and more efficient, preferably Trypanosoma cruzi-specific, chemotherapies would be highly advantageous. We have recently reported that the experimental T. cruzi CYP51 inhibitor VNI cures with 100% survival and 100% parasitological clearance both acute and chronic murine infections with the Tulahuen strain of T. cruzi. In this work, we further explored the potential of VNI by assaying nitro-derivative-resistant T. cruzi strains, Y and Colombiana, in highly stringent protocols of acute infection. The data show high antiparasitic efficacy of VNI and its derivative (VNI/VNF) against both forms of T. cruzi that are relevant for mammalian host infection (bloodstream and amastigotes), with the in vivo potency, at 25 mg/kg twice a day (b.i.d.), similar to that of benznidazole (100 mg/kg/day). Transmission electron microscopy and reverse mutation tests were performed to explore cellular ultrastructural and mutagenic aspects of VNI, respectively. No mutagenic potential could be seen by the Ames test at up to 3.5 μM, and the main ultrastructural damage induced by VNI in T. cruzi was related to Golgi apparatus and endoplasmic reticulum organization, with membrane blebs presenting an autophagic phenotype. Thus, these preliminary studies confirm VNI as a very promising trypanocidal drug candidate for Chagas disease therapy.
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