Efficacy of voriconazole in a murine model of acute Trypanosoma cruzi infection

Gulin, Julián Ernesto Nicolás; Eagleson, Mackenzie A.; Postan, Miriam; Cutrullis, Romina Andrea; Freilij, Héctor; Garcia‐Bournissen, Facundo; Petray, Patricia; Altcheh, Jaime

doi:10.1093/jac/dks478

Cited by 17 publications

(10 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The VD strain was isolated from a pediatric patient with congenital infection. As previously noted from in vivo investigations [ 27 , 28 ], in our study the VD strain seemed more virulent than the CL Brener strain due the faster emergence from infected Vero cells. The hypothetical proteins of unknown function could be involved in virulence, and also be a source of biomarkers candidates for strain discrimination and for further studies to understand the underlying mechanisms of pathogenicity.…”

Section: Discussionsupporting

confidence: 84%

Secretome analysis of Trypanosoma cruzi by proteomics studies

et al. 2017

View full text Add to dashboard Cite

BackgroundChagas disease is a debilitating often fatal disease resulting from infection by the protozoan parasite Trypanosoma cruzi. Chagas disease is endemic in 21 countries of the Americas, and it is an emerging disease in other countries as a result of migration. Given the chronic nature of the infection where intracellular parasites persist for years, the diagnosis of T. cruzi by direct detection is difficult, whereas serologic tests though sensitive may yield false-positive results. The development of new rapid test based on the identification of soluble parasitic antigens in serum would be a real innovation in the diagnosis of Chagas disease.MethodsTo identify new soluble biomarkers that may improve diagnostic tests, we investigated the proteins secreted by T. cruzi using mass spectrometric analyses of conditioned culture media devoid of serum collected during the emergence of trypomastigotes from infected Vero cells. In addition, we compared the secretomes of two T. cruzi strains from DTU Tc VI (VD and CL Brener).ResultsAnalysis of the secretome collected during the emergence of trypomastigotes from Vero cells led to the identification of 591 T. cruzi proteins. Three hundred sixty three proteins are common to both strains and most belong to different multigenic super families (i.e. TcS, GP63, MASP, and DGF1). Ultimately we have established a list of 94 secreted proteins, common to both DTU Tc VI strains that do not belong to members of multigene families.ConclusionsThis study provides the first comparative analysis of the secretomes from two distinct T. cruzi strains of DTU TcVI. This led us to identify a subset of common secreted proteins that could potentially serve as serum markers for T. cruzi infection. Their potential could now be evaluated, with specific antibodies using sera collected from patients and residents from endemic regions.

show abstract

Section: Discussionsupporting

confidence: 84%

Secretome analysis of Trypanosoma cruzi by proteomics studies

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Fluconazole did not cure mice upon treatment with the 200 mg/kg daily dosage for 30 days [57], which in fact is in agreement with its relatively weak inhibitory potency as T. cruzi CYP51 inhibitor in vitro [58,59]. Its close-derivative voriconazole, however, has been recently reported to reveal some suppressive effect in a mouse model (75% survival rate at the 40 mg/kg/day dosage administered for 30 days; Tulahuen strain of T. cruzi ) [60]. …”

Section: Screening Of Existing Antifungal Drugsmentioning

confidence: 58%

Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?

Lepesheva

2013

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

Introduction Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains incurable. In 2012, two antimycotic drugs inhibitors of fungal sterol 14α-demethylase (CYP51) – posaconazole and ravuconazole – entered clinical trials. Availability of the X-ray structure of the orthologous enzyme from the causative agent of the disease, protozoan parasite Trypanosoma cruzi, determined in complexes with posaconazole as well as with several experimental protozoa-specific CYP51 inhibitors opens an excellent opportunity to improve the situation. Areas covered This article summarizes the information available in PubMed and Google on the outcomes of treatment of the chronic Chagas disease. It also outlines the major features of the T. cruzi CYP51 structure and the possible structure-based strategies for rational design of novel T. cruzi specific drugs. Expert opinion There is no doubt that screenings for alternative drug-like molecules as well as mining the T. cruzi genome for novel drug targets are of great value and might eventually lead to groundbreaking discoveries. However, all newly identified molecules must proceed through the long, expensive and low-yielding drug optimization process, and all novel potential drug targets must be validated in terms of their essentiality and druggability. CYP51 is already a well-validated and highly successful target for clinical and agricultural antifungals. With minimal investments into the final stages of their development/trials, T. cruzi-specific CYP51 inhibitors can provide an immediate treatment for Chagas disease, either on their own or in combination with the currently available drugs.

show abstract

“…Voriconazole, an antifungal triazole derivative, has demonstrated in vitro and in vivo activity in a murine model of acute T. cruzi infection, 144 significantly reducing the peak of parasitemia, increasing lifespan, and decreasing mortality compared with nontreated mice. Unfortunately, treatment with voriconazole proved significantly less effective than the reference drug BZ in parasitemia reduction.…”

Section: Methodsmentioning

confidence: 99%

Experimental and Clinical Treatment of Chagas Disease: A Review

Sales

Molina

Murta

et al. 2017

The American Journal of Tropical Medicine and Hygiene

226

128

View full text Add to dashboard Cite

Abstract.Chagas disease (CD) is caused by the protozoan parasite Trypanosoma cruzi that infects a broad range of triatomines and mammalian species, including man. It afflicts 8 million people in Latin America, and its incidence is increasing in nonendemic countries owing to rising international immigration and nonvectorial transmission routes such as blood donation. Since the 1960s, the only drugs available for the clinical treatment of this infection have been benznidazole (BZ) and nifurtimox (NFX). Treatment with these trypanocidal drugs is recommended in both the acute and chronic phases of CD. These drugs have low cure rates mainly during the chronic phase, in addition both drugs present side effects that may result in the interruption of the treatment. Thus, more efficient and better-tolerated new drugs or pharmaceutical formulations containing BZ or NFX are urgently needed. Here, we review the drugs currently used for CD chemotherapy, ongoing clinical assays, and most-promising new experimental drugs. In addition, the mechanism of action of the commercially available drugs, NFX and BZ, the biodistribution of the latter, and the potential for novel formulations of BZ based on nanotechnology are discussed. Taken together, the literature emphasizes the urgent need for new therapies for acute and chronic CD.

show abstract

Efficacy of voriconazole in a murine model of acute Trypanosoma cruzi infection

Abstract: Our findings support the potential of voriconazole for the treatment of acute Chagas' disease and motivate future animal studies using varying doses and treatment schemes. Further evaluation of voriconazole for clinical use in human Chagas' patients is warranted.

Cited by 17 publications

References 21 publications

Secretome analysis of Trypanosoma cruzi by proteomics studies

Secretome analysis of Trypanosoma cruzi by proteomics studies

Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?

Experimental and Clinical Treatment of Chagas Disease: A Review

Contact Info

Product

Resources

About