Discovery of novel drugs for Chagas disease: is carbonic anhydrase a target for antiprotozoal drugs?

ABSTRACT

Introduction

Carbonic anhydrase (CA) arose significant interest as a potential new target for Chagas disease since its discovery in Trypanosoma cruzi in 2013. Benznidazole and Nifurtimox have been used for Chagas disease treatment for 60 years despite all efforts done for obtaining more efficient treatments, acting in the acute and chronic phases of illness, with fewer side effects and resistance induction.

Areas covered

We discuss the positive and negative aspects of T. cruzi CA (TcCA) studies as a target for developing new drugs. The current research discoveries and the classes of TcCA inhibitors are reviewed. The sulfonamides and their derivatives are the main inhibitor classes, but hydroxamates and the thiols, were investigated too. These compounds inhibited the growth of the evolutive forms of the parasite. A comparative analysis was done with CAs from other Trypanosomatids and protozoans.

Expert opinion

The search for new targets and drugs is a significant challenge worldwide, and TcCA is a potential candidate for developing new drugs. Several studied inhibitors were active against Trypanosoma cruzi, but their penetration and toxicity problems emerged. New approaches are in progress to obtain inhibitors with desired properties, allowing further steps such as tests using an adequate animal model and subsequent developments for the preclinical testing.

KEYWORDS:

• Trypanosoma cruzi
• carbonic anhydrase
• TCcA inhibitor
• therapeutic targets

Article highlights

• Trypanosoma cruzi encodes an α-class carbonic anhydrase, TcCA

• TcCA was shown to possess a significant catalytic activity for the physiologic reaction of CO₂ hydration to bicarbonate and protons

• TcCA is inhibited efficiently in vitro by the main classes of CA inhibitors, including sulfonamides and isosteres, anions, thiols, benzoxaboroles, hydroxamates

• In vivo, several TcCA inhibitors showed anti-T. cruzi effects, although the penetration and toxicity of the inhibitors are not optimized

• The validation of TcCA as anti-T. cruzi drug target by using genetic knock-down is difficult if not impossible due to the many developmental stages of the parasite

• The development of more effective and pharmacologically optimized TcCA inhibitors with the evolutive forms of the parasite and in vivo studies need to be completed in order to evaluate TcCA as a novel target and advance to the preclinical tests

This box summarizes key points contained in the article.

Declaration of interest

The authors have 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was financed in part by the postgraduate program of the Paulo de Góes Institute of Microbiology, Federal University of Rio de Janeiro (UFRJ), through the Coordenação de Aperfeiçoamento Pessoal de Nível Superior (CAPES) [grant 001], Conselho Nacional de Desenvolvimento Científico e Tecnológico (MCTI-CNPq) [grant 309461/2019-7], Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro - (FAPERJ) [grant 24708]. and, by the MIUR (Italian Ministry for University 163and Research), projects FISR2019_04819 (BacCAD) and PRIN2017 [rot. 2017XYBP2R] and by Ente Cassa di Risparmio di Firenze (ECRF), grant [CRF2020.1395].