Antichagasic effect of crotalicidin, a cathelicidin-like vipericidin, found in Crotalus durissus terrificus rattlesnake's venom gland

Abstract

Cathelicidins are antimicrobial peptides produced by humans and animals in response to various pathogenic microbes. Crotalicidin (Ctn), a cathelicidin-related vipericidin from the South American Crotalus durissus terrificus rattlesnake's venom gland, and its fragments have demonstrated antimicrobial and antifungal activity, similarly to human cathelicidin LL-37. In order to provide templates for the development of modern trypanocidal agents, the present study evaluated the antichagasic effect of these four peptides (Ctn, Ctn[1-14], Ctn[15-34] and LL-37). Herein, Ctn and short derived peptides were tested against the epimastigote, trypomastigote and amastigote forms of Trypanosoma cruzi Y strain (benznidazole-resistant strain) and cytotoxicity in mammalian cells was evaluated against LLC-MK2 lineage cells. Ctn inhibited all T. cruzi developmental forms, including amastigotes, which is implicated in the burden of infection in the chronic phase of Chagas disease. Moreover, Ctn showed a high selective index against trypomastigote forms (>200). Ctn induced cell death in T. cruzi through necrosis, as determined by flow cytometry analyses with specific molecular probes and morphological alterations, such as loss of membrane integrity and cell shrinkage, as observed through scanning electron microscopy. Overall, Ctn seems to be a promising template for the development of antichagasic agents.

Structural determinants conferring unusual long life in human serum to rattlesnake‐derived antimicrobial peptide Ctn[15‐34]

“…In an active search for linear, stable, and cost-effective AMPs with therapeutic potential, our group has been focusing on Ctn [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34], which preserves the main antimicrobial, antitumoral, and antifungal activities of parental crotalicidin (Ctn), but with substantially improved stability in human serum (t 1/2 , approximately 12 h). [33][34][35][36] Herein we investigate in detail this unusual t 1/2 of Ctn [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and how it bears on its biological profile. Using Ctn [15][16][17][18]...…”

EVALUATION OF THE ANTIBACTERIAL ACTIVITY OF Crotalus durissus terrificus CRUDE VENOM

“…The venoms of various snake species also exhibit antimicrobial activity against gram-positive, gram-negative bacteria, retroviruses, and protozoa, such as Leishmania and Trypanosoma cruzi, especially the enzymatic components such as PLAs2 and metalloproteinases. The enzymes act commonly through the hydrolysis of membrane phospholipids; in addition to L-amino acid oxidases and flavoproteins, whose biological activity results from the induction of oxidative stress (14)(15)(16)(17)(18) .…”

Hitchhiking with Nature: Snake Venom Peptides to Fight Cancer and Superbugs

“…• Cdt-CATH: also named as crotalicidin (Ctn), is a 34-aa peptide from the South American rattlesnake (Crotalus durissus terrificus) venom. Among SV-CATHs identified in pit vipers by Falcão et al [84] (lutzicidin, lachesicidin, batroxicidin, collectively named vipericidins), Ctn has been the most studied, showing potent bactericidal effects against Gram-negative and Gram-positive bacteria (MICs <10 µM) [84], anti-parasitic (anti-trypanosomatid) activity [109], and activity against opportunistic yeasts and dermatophytes, alone or in combination with conventional antifungals [108]. In addition, Ctn has shown potent anti-tumor activity against different leukemia cell lines (IC 50 s <5 µM) [107].…”

“…The general mechanism of Ctn against bacteria or parasites is membrane-related and its ability to interfere and disrupt biological membranes have been extensively described [109,122]. Ctn toxicity to leukemia cells is also linked to its membranolytic effect, although it also seems able to interfere with key intracellular pathways, ultimately contributing to tumor cell death (Pérez-Peinado et al, submitted).…”

“…Ctn [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] lost activity against dermatophytes, but had enhanced activity against pathogenic yeasts, such as several (multi-resistant) Candida species, and acted synergistically with amphotericin B [108,134]. Although Ctn was also able to induce necrosis of all developmental forms of T. cruzi (the Chagas' disease agent), Ctn [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] only retained activity against the trypomastigote form [109]. The fragment also showed antiviral activity against the infectious myonecrosis virus, an epizootic agent that threatens shrimp production in Brazil, and for which no current treatment exists [135].…”