A Computational Methodology to Overcome the Challenges Associated With the Search for Specific Enzyme Targets to Develop Drugs Against Leishmania major.

We present an approach for detecting enzymes that are specific of Leishmania major compared with Homo sapiens and provide targets that may assist research in drug development. This approach is based on traditional techniques of sequence homology comparison by similarity search and Markov modeling; it integrates the characterization of enzymatic functionality, secondary and tertiary protein structures, protein domain architecture, and metabolic environment. From 67 enzymes represented by 42 enzymatic activities classified by AnEnPi (Analogous Enzymes Pipeline) as specific for L major compared with H sapiens, only 40 (23 Enzyme Commission [EC] numbers) could actually be considered as strictly specific of L major and 27 enzymes (19 EC numbers) were disregarded for having ambiguous homologies or analogies with H sapiens. Among the 40 strictly specific enzymes, we identified sterol 24-C-methyltransferase, pyruvate phosphate dikinase, trypanothione synthetase, and RNA-editing ligase as 4 essential enzymes for L major that may serve as targets for drug development. PMID: 28638238 [PubMed]
Source: Bioinformatics and Biology Insights - Category: Bioinformatics Authors: Tags: Bioinform Biol Insights Source Type: research

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CONCLUSIONS: There is a clear correlation between ARM56/58 upregulation and Sb resistance in AT-harbouring patients, suggesting the use of these markers as potential indicators to help the treatment choice and outcome, preventing therapeutic failure. PMID: 31433006 [PubMed - in process]
Source: Memorias do Instituto Oswaldo Cruz - Category: Infectious Diseases Authors: Tags: Mem Inst Oswaldo Cruz Source Type: research
This study aimed to describe the preparation and in vitro evaluation of a surface-modified nanostructured lipid carrier (NLC) using chitosan and dextran for co-delivery of buparvaquone (BPQ) and polymyxin B (PB) against leishmaniasis.MethodsThe NLC was prepared using high-pressure homogenisation. Polymyxin B binding and surface modification with biopolymers were achieved by electrostatic interaction. In vitro cytotoxicity was assessed in mouse peritoneal macrophages, and leishmanicidal activity in amastigotes of Leishmania infantum.ResultsThe performance attributes of BPQ-NLC, BPQ-NLC-PB[A−] (anionic) and BPQ-NLC-PB[...
Source: Journal of Global Antimicrobial Resistance - Category: Infectious Diseases Source Type: research
J-DNA–binding protein 1 (JBP1) contributes to the biosynthesis and maintenance of base J (β-d-glucosyl-hydroxymethyluracil), an epigenetic modification of thymidine (T) confined to pathogenic protozoa such as Trypanosoma and Leishmania. JBP1 has two known functional domains: an N-terminal T hydroxylase (TH) homologous to the 5-methylcytosine hydroxylase domain in TET proteins and a J-DNA–binding domain (JDBD) that resides in the middle of JBP1. Here, we show that removing JDBD from JBP1 results in a soluble protein (Δ-JDBD) with the N- and C-terminal regions tightly associated together in a well-orde...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Protein Structure and Folding Source Type: research
The objective was to evaluate the potential of Fluorescence in Situ Hybridization as a diagnostic method for Cutaneous leishmaniasis in Sri Lanka. Literature on current laboratory tests used to diagnose Cutaneous leishmaniasis in Sri Lanka and globally was reviewed. Sri Lankan data were reviewed systematically following the PRISMA guidelines. A narrative of the results is presented. There is currently no gold standard diagnostic method for Cutaneous leishmaniasis. Fluorescence in Situ Hybridization has been previously applied to detect dermal pathologies including those involving infectious agents, and its use to detect th...
Source: Pathogens and Global Health - Category: International Medicine & Public Health Tags: Pathog Glob Health Source Type: research
Publication date: Available online 21 August 2019Source: Molecular and Biochemical ParasitologyAuthor(s): Luiz Fernando Carvalho-Kelly, André Luiz Gomes-Vieira, Lisvane Paes-Vieira, Amanda Durval Zeferino da Silva, José Roberto Meyer-FernandesAbstractHere we characterize a high-affinity Pi transport system energized by a H+ gradient in Leishmania amazonensis. Pi uptake and transcription of LamPho84 gene are differentially regulated during parasite life cycle. Our data suggest that Pi acquisition could be a pivotal task for the success of the parasite throughout its life cycle.Graphical abstract
Source: Molecular and Biochemical Parasitology - Category: Parasitology Source Type: research
Publication date: Available online 21 August 2019Source: International Journal for Parasitology: Drugs and Drug ResistanceAuthor(s): M. Shamim Hasan Zahid, Monica M. Johnson, Robert J. Tokarski, Abhay R. Satoskar, James R. Fuchs, Eric M. Bachelder, Kristy M. AinslieAbstractVisceral leishmaniasis (VL) is associated with treatment complications due to the continued growth of resistant parasites toward currently available pathogen-directed therapeutics. To limit the emergence and combat resistant parasites there is a need to develop new anti-leishmanial drugs and alternative treatment approaches, such as host-directed therape...
Source: International Journal for Parasitology: Drugs and Drug Resistance - Category: Parasitology Source Type: research
Authors: Siriwardana Y, Deepachandi B, Weliange SS, Udagedara C, Wickremarathne C, Warnasuriya W, Ranawaka RR, Kahawita I, Chandrawansa PH, Karunaweera ND Abstract Cutaneous leishmaniasis caused by a genetic variant of L. donovani is being reported from Sri Lanka since year 2001. Patients presented from different geographical locations (600 patients from North or South and a minority of cases from other foci, 2001-2013) were studied. Analysis revealed two different sociodemographic and clinical profiles of leishmaniasis in Northern and Southern Sri Lanka. Also, the same different profiles were present in these foci...
Source: Journal of Tropical Medicine - Category: Tropical Medicine Tags: J Trop Med Source Type: research
Protozoan parasites represent a major threat to health and contribute significantly to morbidity and mortality worldwide, especially in developing countries. This is further compounded by lack of effective vaccines, drug resistance and toxicity associated with current therapies. Multiple protozoans, including Plasmodium, Entamoeba, Toxoplasma, and Leishmania produce homologs of the cytokine MIF. These parasite MIF homologs are capable of altering the host immune response during infection, and play a role in immune evasion, invasion and pathogenesis. This minireview outlines well-established and emerging literature on the r...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
This study showed the antileishmanial activity of compounds 1 and 2 isolated from N. oppositifolia. Furthermore, compound 2 demonstrated an antileishmanial activity towards amastigotes associated to an immunomodulatory effect.
Source: Journal of Venomous Animals and Toxins including Tropical Diseases - Category: Tropical Medicine Source Type: research
Abstract In India, visceral leishmaniasis (VL) caused by Leishmania donovani has been successfully treated with miltefosine with a cure rate of> 90%. To assess the efficacy and safety of oral miltefosine against Brazilian VL, which is caused by Leishmania infantum, a phase II, open-label, dose-escalation study of oral miltefosine was conducted in children (aged 2-12 years) and adolescent-adults (aged 13-60 years). Definitive cure was assessed at a 6-month follow-up visit. The cure rate was only 42% (6 of 14 patients) with a recommended treatment of 28 days and 68% (19 of 28 patients) with an extended treatment ...
Source: The American Journal of Tropical Medicine and Hygiene - Category: Tropical Medicine Authors: Tags: Am J Trop Med Hyg Source Type: research
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