Drug targets in Leishmania

Chawla, Bhavna; Madhubala, Rentala

doi:10.1007/s12639-010-0006-3

Cited by 170 publications

(129 citation statements)

References 94 publications

(77 reference statements)

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“…Therefore, the development of alternative drugs for the treatment of the different clinical forms of leishmaniasis is a priority for controlling the disease (Croft et al 2006;Castillo et al 2010). Great efforts have been made to identify potential chemotherapeutic targets in the genome and proteome of Leishmania sp., in the hope of devising more effective treatments (Myler 2008;Concu et al 2009;Chawla and Madhubala 2010). Proteolytic enzymes or proteinases play an essential role in the parasite's survival.…”

Section: Introductionmentioning

confidence: 99%

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Perteguer

Gómez‐Puertas

Cañavate

et al. 2013

Cell Stress and Chaperones

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Eukaryotic cells respond to DNA damage by activating damage checkpoint pathways, which arrest cell cycle progression and induce gene expression. We isolated a full-length cDNA encoding a 49-kDa protein from Leishmania major, which exhibited significant deduced amino acid sequence homology with the annotated Leishmania sp. DNA damage-inducible (Ddi1-like) protein, as well as with the Ddi1 protein from Saccharomyces cerevisiae. In contrast to the previously described Ddi1 protein, the protein from L. major displays three domains: (1) an NH2-terminal ubiquitin like; (2) a COOH terminal ubiquitinassociated; (3) a retroviral aspartyl proteinase, containing the typical D[S/T]G signature. The function of the L. major Ddi1-like recombinant protein was investigated after expression in baculovirus/insect cells and biochemical analysis, revealing preferential substrate selectivity for aspartyl proteinase A 2 family substrates, with optimal activity in acidic conditions. The proteolytic activity was inhibited by aspartyl proteinase inhibitors. Molecular modeling of the retroviral domain of the Ddi1-like Leishmania protein revealed a dimer structure that contained a double AspSer-Gly-Ala amino acid sequence motif, in an almost identical geometry to the exhibited by the homologous retroviral aspartyl protease domain of yeast Ddi1 protein. Our results indicate that the isolated Ddi1-like protein is a functional aspartyl proteinase in L. major, opening possibility to be considered as a potential target for novel antiparasitic drugs.

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Section: Introductionmentioning

confidence: 99%

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Perteguer

Gómez‐Puertas

Cañavate

et al. 2013

Cell Stress and Chaperones

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“…The first step in drug discovery is to identify a suitable drug target that should be necessary for the survival of the pathogen and should be either absent from the host or substantially different from the host homolog (23). The intracellular pathogen Leishmania exhibits a strong antioxidant defense mechanism by using hemoproteins such as APx of the glutathione-ascorbate cycle for its survival and replication against the oxidants (H 2 O 2 ) released by the macrophage under oxidative burst conditions (10).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of Antileishmanial Activity of Computationally Screened Compounds against Ascorbate Peroxidase To Combat Amphotericin B Drug Resistance

Mansuri

Kumar

Rana

et al. 2017

Antimicrob Agents Chemother

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In visceral leishmaniasis (VL), the host macrophages generate oxidative stress to destroy the pathogen, while Leishmania combats the harmful effect of radicals by redox homeostasis through its unique trypanothione cascade. Leishmania donovani ascorbate peroxidase (LdAPx) is a redox enzyme that regulates the trypanothione cascade and detoxifies the effect of H 2 O 2 . The absence of an LdAPx homologue in humans makes it an excellent drug target. In this study, the homology model of LdAPx was built, including heme, and diverse compounds were prefiltered (PAINS, ADMET, and Lipinski's rule of five) and thereafter screened against the LdAPx model. Compounds having good affinity in terms of the Glide XP (extra precision) score were clustered to select diverse compounds for experimental validation. A total of 26 cluster representatives were procured and tested on promastigote culture, yielding 12 compounds with good antileishmanial activity. Out of them, six compounds were safer on the BALB/c peritoneal macrophages and were also effective against disease-causing intracellular amastigotes. Three out of six compounds inhibited recombinant LdAPx in a noncompetitive manner and also demonstrated partial reversion of the resistance property in an amphotericin B (AmB)-resistant strain, which may be due to an increased level of reactive oxygen species (ROS) and decrease of glutathione (GSH) content. However, inhibition of LdAPx in resistant parasites enhanced annexin V staining and activation of metacaspase-like protease activity, which may help in DNA fragmentation and apoptosis-like cell death. Thus, the present study will help in the search for specific hits and templates of potential therapeutic interest and therefore may facilitate the development of new drugs for combination therapy against VL.KEYWORDS ascorbate peroxidase, phylogenetic analysis, virtual screening and docking, apoptosis, inhibitors, leishmania, enzymatic assay V isceral leishmaniasis (VL) is one of the fatal neglected parasitic diseases and is caused by the flagellated protozoan parasite of the genus Leishmania and family Trypanosomatidae (1). The promastigote forms are transmitted to the host blood through the bite of phlebotomine sand flies (vector) and are differentiated into amastigotes in macrophages, resulting in hepatosplenomegaly (2). According to a WHO report from 2015, approximately 30,000 annual deaths and over 1.3 million new cases were estimated. The countries most affected by VL were noted as Bangladesh, Brazil,

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“…Thus, topoisomerase inhibitors or poisons have been shown to have activity against trypanosomatid protozoa, mediating apoptosis-like death (Smirlis et al 2010 ). Moreover, the antileishmanial compounds sodium stibogluconate and urea stibamine have been shown to act via the inhibition of type I topoisomerase (Chawla and Madhubala 2010 ). Camptothecin, a drug that acts as a poison against leishmanial topoisomerase I ( Das et al 2006a ), has been found to block L .…”

Section: Topoisomerasesmentioning

confidence: 99%

Selection of Molecular Targets for Drug Development Against Trypanosomatids

Smirlis

Soares

2013

Subcellular Biochemistry

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Trypanosomatid parasites are a group of flagellated protozoa that includes the genera Leishmania and Trypanosoma, which are the causative agents of diseases (leishmaniases, sleeping sickness and Chagas disease) that cause considerable morbidity and mortality, affecting more than 27 million people worldwide. Today no effective vaccines for the prevention of these diseases exist, whereas current chemotherapy is ineffective, mainly due to toxic side effects of current drugs and to the emergence of drug resistance and lack of cost effectiveness. For these reasons, rational drug design and the search of good candidate drug targets is of prime importance. The search for drug targets requires a multidisciplinary approach. To this end, the completion of the genome project of many trypanosomatid species gives a vast amount of new information that can be exploited for the identification of good drug candidates with a prediction of "druggability" and divergence from mammalian host proteins. In addition, an important aspect in the search for good drug targets is the "target identification" and evaluation in a biological pathway, as well as the essentiality of the gene in the mammalian stage of the parasite, which is provided by basic research and genetic and proteomic approaches. In this chapter we will discuss how these bioinformatic tools and experimental evaluations can be integrated for the selection of candidate drug targets, and give examples of metabolic and signaling pathways in the parasitic protozoa that can be exploited for rational drug design.

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Drug targets in Leishmania

Cited by 170 publications

References 94 publications

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

Ddi1-like protein from Leishmania major is an active aspartyl proteinase

In Vitro Evaluation of Antileishmanial Activity of Computationally Screened Compounds against Ascorbate Peroxidase To Combat Amphotericin B Drug Resistance

Selection of Molecular Targets for Drug Development Against Trypanosomatids

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