Antimicrobial Peptides (AMPs): Potential Therapeutic Strategy against Trypanosomiases?

Abstract

Trypanosomiases are a group of tropical diseases that have devastating health and socio-economic effects worldwide. In humans, these diseases are caused by the pathogenic kinetoplastids Trypanosoma brucei, causing African trypanosomiasis or sleeping sickness, and Trypanosoma cruzi, causing American trypanosomiasis or Chagas disease. Currently, these diseases lack effective treatment. This is attributed to the high toxicity and limited trypanocidal activity of registered drugs, as well as resistance development and difficulties in their administration. All this has prompted the search for new compounds that can serve as the basis for the development of treatment of these diseases. Antimicrobial peptides (AMPs) are small peptides synthesized by both prokaryotes and (unicellular and multicellular) eukaryotes, where they fulfill functions related to competition strategy with other organisms and immune defense. These AMPs can bind and induce perturbation in cell membranes, leading to permeation of molecules, alteration of morphology, disruption of cellular homeostasis, and activation of cell death. These peptides have activity against various pathogenic microorganisms, including parasitic protists. Therefore, they are being considered for new therapeutic strategies to treat some parasitic diseases. In this review, we analyze AMPs as therapeutic alternatives for the treatment of trypanosomiases, emphasizing their possible application as possible candidates for the development of future natural anti-trypanosome drugs.

Neglected Zoonotic Diseases: Advances in the Development of Cell-Penetrating and Antimicrobial Peptides against Leishmaniosis and Chagas

“…The conventional treatment of these diseases has important limitations, since many of the drugs are from the early and mid 20th century, and have limited efficacy in advanced stages of the disease, and are nonspecific and/or highly toxic [12]. Therefore, the goal of finding new starting points for developing new drugs to effectively treat and control these diseases is a priority [12,13]. To overcome these deficiencies, AMPs and CPPs could become a promising alternative for pharmaceutical design and treatment of intracellular infectious diseases.…”

“…Direct penetration is a highly limited entry pathway for conventional drugs, preventing them from exerting their action on their target [24]. However, the peptides can use this route of entry, accumulating locally in the parasite and reaching the necessary concentration to be effective [13]. The cell membranes of these pathogens have an outer hemilayer with a higher percentage of anionic phospholipids, providing global negative charge to the surface.…”

“…Notably, the usage of the different pathways depends on the combination of cell surface receptors and on the size of the cargo to be internalized [23]. The detailed mechanism of AMPs and/or CPPs internalization is not fully clear, but some hints have been elucidated [13]. Parasite phospholipases (PLA2) are involved in regulating the vesicular traffic, by modifying the membrane phospholipids and inducing the membrane deformation to generate the vesicles [29].…”

“…Another useful property of AMPs is their ability to stimulate the host immune response, which can help to eliminate the infecting pathogen and promote the clearance of infected cells [13]. This broad-spectrum activity makes them particularly useful for treating infections caused by complex microorganisms like Leishmania or T. cruzi.…”

“…The results make Ctn a promising lead for the development of new peptide-based drugs to treat Chagas disease. Two fragments of the AMP M-PONTX-Dq3a, isolated from the Dinoponera quadriceps ant venom are M-PONTX-Dq3a [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] and [Lys] 3 -M-PONTX-Dq3a [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Both fragments have been demonstrated to possess trypanocidal activities similar to those of the parent peptide against all three forms of T. cruzi Y strain but with lower toxicity, better bioavailability and lower cost of production [144,145].…”