Cm-p5, a synthetic antimicrobial peptide shows anti-Trypanosoma cruzi activity

TL;DR

A synthetic antimicrobial peptide called Cm-p5 shows strong anti-Trypanosoma cruzi activity, making it a promising candidate for treating Chagas disease.

Contribution

Cm-p5 is a novel synthetic peptide with potent trypanocidal effects and low cytotoxicity, offering a new potential treatment for Chagas disease.

Findings

Cm-p5 has an EC50 of 16.9 μM against T. cruzi epimastigotes and 25.2 μM against intracellular amastigotes.

Cm-p5 reduces the release of infective trypomastigotes and decreases the infection index by 91.1%.

The peptide induces cell cycle arrest and membrane damage in T. cruzi.

Abstract

Chagas disease is a neglected disease caused by Trypanosoma cruzi, which affects 6–7 million people worldwide. More than one hundred years after its description, the performance of available drugs for treating the T. cruzi infection remains largely unsatisfactory. Antimicrobial peptides (AMPs) are new alternatives that may have potential as trypanocides. Herein, we assessed Cm-p5, a synthetic peptide with previously shown antimicrobial activity, and 10 derivatives. After screening assays using epimastigote forms of the parasite to test their potential as proliferation inhibitors, Cm-p5 was selected. Cm-p5 showed an EC50 against T. cruzi of 16.9 ± 1.2 μM and a cytotoxicity towards CHO-K1 mammalian cells (CC50) of 124.8 ± 0.1 µM. After further investigation, it was evidenced that part of the epimastigote population underwent necrosis-like cell death, while those that remained alive showed a cell-cycle arrest at the phases G2_M and S_G2. When infected cells were treated, the peptide diminished the release of the infective trypomastigote form, with an EC50 of 25.2 ± 1.4 µM. Furthermore, Cm-p5 inhibited the number of intracellular amastigotes as well as the number of infected cells by 64.3 and 75%, respectively. Taken together, these numbers resulted in a reduction of the infection index by 91.1%. Additionally, we showed that Cm-p5 trypanocidal activity against intracellular amastigotes was attributable to cell membrane damage and cell cycle partial arrest, as described for epimastigotes. Our data suggest that Cm-p5 may be a promising template to design new peptides for the treatment of Chagas disease.

Trypanosoma cruzi, a hemoflagellate parasite that belongs to the group of kinetoplastids, causes Chagas disease. It is estimated that 7 million people are infected and therefore more than 75 million people are at risk of acquiring Chagas disease. Only two drugs are available for its treatment, nifurtimox and benznidazole, which have limitations regarding efficacy and tolerance. Therefore, there is an urgent need for new molecules with anti-T. cruzi potential. In this work, we assessed Cm-p5 and 10 derivatives and their potential as a trypanocidal drug. Cm-p5 is a synthetic peptide with antimicrobial activity, which showed a potent effect on the intracellular forms of the parasite (EC50 of 25.2 ± 1.4 µM) and inhibits the intracellular cycle of T. cruzi. This peptide could be a promising alternative to the development of new peptides to improve the chemotherapy of Chagas disease.

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