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J. Biol. Chem., Vol. 280, Issue 2, 984-990, January 14, 2005

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Temporins, Small Antimicrobial Peptides with Leishmanicidal Activity^*

Maria Luisa Mangoni, José M. Saugar¶, Maria Dellisanti, Donatella Barra||, Maurizio Simmaco, and Luis Rivas¶

From the Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli," Azienda Ospedaliera S. Andrea, ^||CNR Istituto di Biologia e Patologia Molecolari, Università "La Sapienza," Piazzale Aldo Moro 5, 00185 Rome, Italy, and ^¶Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, E-28040 Madrid, Spain

Leishmaniasis encompasses a wide range of infections caused by the human parasitic protozoan species belonging to the Leishmania genus. It appears frequently as an opportunistic disease, especially in virus-infected immunodepressed people. Similarly to other pathogens, parasites became resistant to most of the first-line drugs. Therefore, there is an urgent need to develop antiparasitic agents with new modes of action. Gene-encoded antimicrobial peptides are promising candidates, but so far only a few of them have shown anti-protozoa activities. Here we found that temporins A and B, 13-amino acid antimicrobial peptides secreted from the skin of the European red frog Rana temporaria, display anti-Leishmania activity at micromolar concentrations, with no cytolytic activity against human erythrocytes. To the best of our knowledge, temporins represent the shortest natural peptides having the highest leishmanicidal activity and the lowest number of positively charged amino acids (a single lysine/arginine) and maintain biological function in serum. Their lethal mechanism involves plasma membrane permeation based on the following data. (i) They induce a rapid collapse of the plasma membrane potential. (ii) They induce the influx of the vital dye SYTOX^TM Green. (iii) They reduce intracellular ATP levels. (iv) They severely damage the membrane of the parasite, as shown by transmission electron microscopy. Besides giving us basic important information, the unique properties of temporins, as well as their membranolytic effect, which should make it difficult for the pathogen to develop resistance, suggest them as potential candidates for the future design of antiparasitic drugs with a new mode of action.

Received for publication, September 20, 2004 , and in revised form, October 26, 2004.

^* This work was supported by grants from the Italian Ministero dell'Istruzione, dell'Università e della Ricerca, Università La Sapienza, and the Spanish Ministry of Science and Technology Grant BIO2003-09056-CO2-2, the Comunidad Autonoma de Madrid Grant 08.2/0054/2001.02, Plan Estratégico de Grupos en Biotecnología, and Grant CO3/14 Red Española de Investigación en Patología Infecciosa from Fondo de Investigaciones Sanitarias. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dipartimento di Scienze Biochimiche, Università La Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy. Tel.: 39-06-8034-5457; Fax: 39-06-8034-5405; E-mail: marialuisa.mangoni{at}uniroma1.it.

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