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Leishmania (L.) infantum causes visceral, cutaneous, and mucosal leishmaniasis in humans and canine leishmaniasis in dogs. Herein, we describe that O-alkyl hydroxamate derivatives displayed potent and selective in vitro activity against the amastigote stage of L. infantum while no activity was observed against promastigotes. Compound 5 showed potent in vivo activity against L. infantum. Moreover, the combination of compound 5 supported on gold nanoparticles and meglumine antimoniate was also effective in vivo and improved the activity of these compounds compared to that of the individual treatment. Docking studies showed that compound 5 did not reach highly conserved pocket C and established interactions with the semiconserved residues V44, A45, R242, and E243 in pocket A of LiSIR2rp1. The surface space determined by these four amino acids is not conserved in human sirtuins. Compound 5 represents a new class of selective ligands with antileishmanial activity.

In recent years there has been growing interest in analyzing the geographical variations between populations of different Phlebotomus spp. by comparing the sequences of various genes However, little is known about the genetic structure of Phlebotonnis arias,. In this study, we were able to sequence a fragment of the mitochondrial Cyt b gene in 133 sandflies morphologically identified as P anasi and proceeding from a wide geographical range covering 35 locations in 11 different regions from five countries. The intra-specific diversity of P. anasi is high, with 45 haplotypes differing from each other by one to 26 bases and they are distributed in two mitochondria' lineages, one limited geographically to Algeria and the other widely dispersed across Mediterranean countries The Algerian lineage is characterized by having 13 fixed polymorphisms and is made up of one sole haplotype. The European/Moroccan P. anasz lineage is characterized by being made up of a great diversity of haplotypes (44) which display some geographical structuring. This could be one of the multiple factors involved in the epidemiological heterogeneity of the foci of leishmaniasis Phlebotomus choral, is the sister group of European/Moroccan P. anasi. The separation of the Algerian haplotype, H45, from the rest of the specimens, European/Moroccan P anon and P chadln, is well supported by the bootstrap analysis (C) 2010 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

A caracterização de sequências codificadoras presentes nas vizinhanças do gene META 1 permitiu a identificação de alguns genes expressos preferencialmente em estágios infectivos de L. (L.) amazonensis. Um dos genes presentes é regulado de forma distinta, observando-se maior abundância do RNA em formas amastigotas. Este gene foi denominado LaLRR17 por codificar uma proteína contendo em sua região central 6 repetições ricas em leucina (LRR). As LRR são motivos presentes em diversas famílias de proteínas e são responsáveis pela formação de uma estrutura capaz de estabelecer interações protéicas. A região central da proteína LRR17 apresentou similaridade com a porção carboxi-terminal da proteína NOD 3 humana. A proteína LRR17 foi localizada no citosol de macrófagos infectados com L. (L.) amazonensis. Para caracterizar a função da proteína LRR17 foram obtidas linhagens de L. (L.) amazonensis expressoras do gene LmjLRR17. Essas linhagens mutantes foram mais infectivas em macrófagos in vitro quando comparadas com a linhagem selvagem. Avaliamos também o papel das proteínas NOD 1 e NOD 2 na infecção por L. (L.) amazonensis e L. (L.) major para estabelecer a possível relação da proteína LRR17 na interação com essas vias de defesa celular do macrófago. The characterization of coding sequences in the vicinity of the META 1 gene allowed the identification of some genes preferentially expressed in L. (L.) amazonensis infective stages. One of the identified transcripts presents a distinct pattern of expression with higher levels of mRNA in amastigotes. This gene was named LaLRR17 since it encodes a 72 kDa protein with 6 leucine-rich repeats (LRR) in its central region. Leucine-rich repeats (LRR) are present in several families of proteins and are responsible for the formation of a structure capable of establishing protein interactions. The central region of the LRR17 protein showed similarity with the carboxyl-terminal portion of the NOD 3 human protein. The LaLRR17 protein is secreted to the cytoplasm of L. (L.) amazonensis-infected macrophages. To characterize the function of the LRR17 protein we obtained strains of L. (L.) amazonensis expressing the LmjLRR17 gene. These mutant strains were more infective to macrophages in vitro when compared with the wild type strain. We also evaluated the role of NOD 1 and NOD 2 proteins in infections with L. (L.) amazonensis and L. (L.) major to investigate a possible role of the LRR17 protein in the interaction with these defense pathways in macrophages.