Efficacy of Synthetic Peptides RP-1 and AA-RP-1 against Leishmania Species In Vitro and In Vivo Marie Crisel B. Erfe a , Consuelo V. David a , b , c , Cher Huang a , Victoria Lu a , Ana Claudia Maretti-Mira a , d , Jacquelyn Haskell a , Kevin W. Bruhn a , e , Michael R. Yeaman a , e and Noah Craft a , e a Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA b London School of Hygiene and Tropical Medicine, London, United Kingdom c University of Maryland School of Medicine, Baltimore, Maryland, USA d Laboratory of Interdisciplinary Medical Research, Instituto Oswaldo Cruz at Fiocruz, Rio de Janeiro, Brazil e David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA 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.
Efficacy of Synthetic Peptides RP-1 and AA-RP-1 against Leishmania Species In Vitro and In Vivo
Abstract
Efficacy of Synthetic Peptides RP-1 and AA-RP-1 against Leishmania Species In Vitro and In Vivo Marie Crisel B. Erfe a , Consuelo V. David a , b , c , Cher Huang a , Victoria Lu a , Ana Claudia Maretti-Mira a , d , Jacquelyn Haskell a , Kevin W. Bruhn a , e , Michael R. Yeaman a , e and Noah Craft a , e a Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA b London School of Hygiene and Tropical Medicine, London, United Kingdom c University of Maryland School of Medicine, Baltimore, Maryland, USA d Laboratory of Interdisciplinary Medical Research, Instituto Oswaldo Cruz at Fiocruz, Rio de Janeiro, Brazil e David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA 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.Preview Only. This article cannot be rented because we do not currently have permission from the publisher.
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Efficacy of Synthetic Peptides RP-1 and AA-RP-1 against Leishmania Species In Vitro and In Vivo
Erfe, Marie Crisel B.; David, Consuelo V.; Huang, Cher; Lu, Victoria; Maretti-Mira, Ana Claudia; Haskell, Jacquelyn; Bruhn, Kevin W.; Yeaman, Michael R.; Craft, Noah
Follow Antimicrobial Agents and Chemotherapy
, Volume 56 (2): 658
American Society For Microbiology – Feb 1, 2012
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