title: Efficacy of synthetic peptides RP-1 and AA-RP-1 against Leishmania species in vitro and in vivo.
abstract: Host defense peptides are naturally occurring molecules that play essential roles in innate immunity to infection. Based on prior structure-function knowledge, we tested two synthetic peptides (RP-1 and AA-RP-1) modeled on the conserved, microbicidal α-helical domain of mammalian CXCL4 platelet kinocidins. These peptides were evaluated for efficacy against Leishmania species, the causative agents of the group of diseases known as leishmaniasis. In vitro antileishmanial activity was assessed against three distinct Leishmania strains by measuring proliferation, metabolic activity and parasite viability after exposure to various concentrations of peptides. We demonstrate that micromolar concentrations of RP-1 and AA-RP-1 caused dose-dependent growth inhibition of Leishmania promastigotes. This antileishmanial activity correlated with rapid membrane disruption, as well as with a loss of mitochondrial transmembrane potential. In addition, RP-1 and AA-RP-1 demonstrated distinct and significant in vivo antileishmanial activities in a mouse model of experimental visceral leishmaniasis after intravenous administration. These results establish efficacy of RP-1 lineage synthetic peptides against Leishmania species in vitro and after intravenous administration in vivo and provide further validation of proof of concept for the development of these and related systemic anti-infective peptides targeting pathogens that are resistant to conventional antibiotics.
authors: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
authors: Marie Crisel B
authors: MC
authors: Erfe
authors: Consuelo V
authors: CV
authors: David
authors: Cher
authors: C
authors: Huang
authors: Victoria
authors: V
authors: Lu
authors: Ana Claudia
authors: AC
authors: Maretti-Mira
authors: Jacquelyn
authors: J
authors: Haskell
authors: Kevin W
authors: KW
authors: Bruhn
authors: Michael R
authors: MR
authors: Yeaman
authors: Noah
authors: N
authors: Craft
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects / Q000469:parasitology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007891:Leishmania / Q000145:classification / Q000187:drug effects* / Q000254:growth & development; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D021261:Parasitic Sensitivity Tests; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010978:Platelet Factor 4; D016896:Treatment Outcome
chemical_list: D023181:Antimicrobial Cationic Peptides; D000981:Antiprotozoal Agents; D010455:Peptides; C541455:RP-1 peptide; D010978:Platelet Factor 4