title: Inhibition of malaria parasite Plasmodium falciparum development by crotamine, a cell penetrating peptide from the snake venom.
abstract: We show here that crotamine, a polypeptide from the South American rattlesnake venom with cell penetrating and selective anti-fungal and anti-tumoral properties, presents a potent anti-plasmodial activity in culture. Crotamine inhibits the development of the Plasmodium falciparum parasites in a dose-dependent manner [IC50 value of 1.87 μM], and confocal microscopy analysis showed a selective internalization of fluorescent-labeled crotamine into P. falciparum infected erythrocytes, with no detectable fluorescence in uninfected healthy erythrocytes. In addition, similarly to the crotamine cytotoxic effects, the mechanism underlying the anti-plasmodial activity may involve the disruption of parasite acidic compartments H(+) homeostasis. In fact, crotamine promoted a reduction of parasites organelle fluorescence loaded with the lysosomotropic fluorochrome acridine orange, in the same way as previously observed mammalian tumoral cells. Taken together, we show for the first time crotamine not only compromised the metabolism of the P. falciparum, but this toxin also inhibited the parasite growth. Therefore, we suggest this snake polypeptide as a promising lead molecule for the development of potential new molecules, namely peptidomimetics, with selectivity for infected erythrocytes and ability to inhibit the malaria infection by its natural affinity for acid vesicles.
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: S
authors.initials: S
authors.lastname: El Chamy Maluf
authors.affiliation: Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: C
authors.initials: C
authors.lastname: Dal Mas
authors.affiliation: Departamento de Bioquímica e Imunologia, Universidade de São Paulo (USP-RP), Ribeirão Preto, Brazil.
authors.forename: E B
authors.initials: EB
authors.lastname: Oliveira
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: P M
authors.initials: PM
authors.lastname: Melo
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil.
authors.forename: A K
authors.initials: AK
authors.lastname: Carmona
authors.affiliation: Departamento de Biociências, Universidade Federal de São Paulo (UNIFESP), Santos, SP, Brazil. Electronic address: marcos.gazarini@gmail.com.
authors.forename: M L
authors.initials: ML
authors.lastname: Gazarini
authors.affiliation: Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil. Electronic address: mhayashi.unifesp@gmail.com.
authors.forename: M A F
authors.initials: MA
authors.lastname: Hayashi
mesh_terms: D000165:Acridine Orange / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000302:isolation & purification / Q000494:pharmacology*; D001692:Biological Transport; D002232:Carbocyanines / Q000737:chemistry; D057846:Cell-Penetrating Peptides / Q000302:isolation & purification / Q000494:pharmacology*; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D003435:Crotalid Venoms / Q000302:isolation & purification / Q000494:pharmacology*; D017839:Crotalus / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D012910:Snake Venoms / Q000737:chemistry*; D013194:Staining and Labeling; D014617:Vacuoles / Q000187:drug effects / Q000469:parasitology
chemical_list: D000962:Antimalarials; D002232:Carbocyanines; D057846:Cell-Penetrating Peptides; D003435:Crotalid Venoms; D005456:Fluorescent Dyes; D012910:Snake Venoms; C089187:cyanine dye 3; D002738:Chloroquine; C010563:crotamine; D000165:Acridine Orange
keywords: Acidic compartments; Antimalarial; Crotamine; Parasites; Peptide trafficking; Plasmodium