Detection and treatment of Trypanosoma cruzi: a patent review (2011-2015)

ABSTRACT

Introduction: Trypanosoma cruzi is the etiologic agent of American trypanosomiasis (Chagas disease), which is one of the important parasitic diseases worldwide. The number of infected people with T. cruzi diminished from 18 million in 1991 to 6 million in 2010, but it is still the most prevalent parasitic disease in the Americas. The existing chemotherapy is still deficient and based on two drugs: nifurtimox and benznidazole, which are not FDA-approved in the United States.

Areas covered: This review covers the current and future directions of Chagas disease chemotherapy based on drugs that interfere with relevant metabolic pathways. This article also illustrates the challenges of diagnosis, which in recent infections, is only detected when the parasitemia is high (direct detection); whereas, in the chronic phase is reached after multiple serological tests.

Expert opinion: The current chemotherapy is associated with long term treatments and severe side effects. Nifurtimox and benznidazole are able to cure at least 50% of recent infections. Nevertheless, they suffer from major drawbacks: selective drug sensitivity on different T. cruzi strains and serious side effects. The aim of this review is focused on presenting an up-to-date status of the chemotherapy and diagnosis.

KEYWORDS:

• Trypanosoma cruzi
• Chagas disease
• drug discovery
• drug treatment
• antiparasitic agents
• diagnosis

Article highlights

• Chagas disease is a parasitic illness produced by Trypanosoma cruzi, endemic from southern United States to southern South America.

• The current treatment for Chagas disease involves the use of two empirically discovered drugs: nifurtimox and benznidazole, which present severe side effects and are not FDA approved.

• The development of putative drugs exploits the metabolic differences between the parasite and the host.

• Drugs have been developed targeting several metabolic pathways, with many key enzymes present: Δ²⁴⁽²⁵⁾-sterol methyltransferase, 14α-demethylase (CYP51), squalene epoxidase, squalene synthase, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, farnesyl pyrophosphate synthase, cysteine proteinases, trypanothione biosynthesis, Fe-superoxide dismutase, protein kinases and trans-sialidase.

• Some drugs have non-identified targets such as those producing oxygen active species, analogues of ML341 and lychnopholide.

• Currently, only two drugs have progressed into clinical trials: posaconazole and the prodrug of ravuconazole E1224.

• Patents filed regarding the diagnosis of the disease utilize biochemical tools such as antigenic polypeptides, oligonucleotide sequences and the detection of T. cruzi antibodies.

This box summarizes key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) (PIP 112-201101-00797), Agencia Nacional de Promoción Científica y Tecnológica (PICT 2012 #0457), and the Universidad de Buenos Aires (20020130100223BA).