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https://www.readbyqxmd.com/read/28647378/leishmaniasis-drug-discovery-recent-progress-and-challenges-in-assay-development
#1
REVIEW
Bilal Zulfiqar, Todd B Shelper, Vicky M Avery
Leishmaniasis, caused by the trypanosomatid protozoan Leishmania, is endemic in 98 countries worldwide, with morbidity and mortality increasing daily. Despite available drugs, leishmaniasis faces the challenge of emerging resistance and toxicity concerns for current drug regimes. Identification of anti-leishmanial compounds representing new chemistry and novel mechanisms of action is essential to populate the drug discovery pipeline. The in vitro assays currently available have shown poor translational outcomes, with high compound attrition rates...
June 21, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28623350/multiplexed-spliced-leader-sequencing-a-high-throughput-selective-method-for-rna-seq-in-trypanosomatids
#2
Bart Cuypers, Malgorzata A Domagalska, Pieter Meysman, Géraldine de Muylder, Manu Vanaerschot, Hideo Imamura, Franck Dumetz, Thomas Wolf Verdonckt, Peter J Myler, Gowthaman Ramasamy, Kris Laukens, Jean-Claude Dujardin
High throughput sequencing techniques are poorly adapted for in vivo studies of parasites, which require prior in vitro culturing and purification. Trypanosomatids, a group of kinetoplastid protozoans, possess a distinctive feature in their transcriptional mechanism whereby a specific Spliced Leader (SL) sequence is added to the 5'end of each mRNA by trans-splicing. This allows to discriminate Trypansomatid RNA from mammalian RNA and forms the basis of our new multiplexed protocol for high-throughput, selective RNA-sequencing called SL-seq...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28608214/use-of-zymography-in-trypanosomiasis-studies
#3
Jéssyka Fernanda Santiago Monte, Cláudia Jassica Gonçalves Moreno, Joana Patrícia Molato Figueiredo Lopes Monteiro, Hugo Alexandre de Oliveira Rocha, Aline Rimoldi Ribeiro, Marcelo Sousa Silva
Zymography assay is a semiquantitative technique, very sensitive, and commonly used to determine metalloproteinase levels in different types of biological samples, including tissues, cells, and extracts of protein. Samples containing metalloproteinases are loaded onto a polyacrylamide gel containing sodium dodecyl sulphate (SDS) and a specific substrate (gelatin, casein, collagen, etc.). Then proteins are allowed to migrate under an electric current and the distance of migration is inversely correlated with the molecular weight...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28601067/minicircle-kinetoplast-genome-of-insect-trypanosomatid-leptomonas-pyrrhocoris
#4
E S Gerasimov, A A Gasparyan, I A Litus, M D Logacheva, A A Kolesnikov
We present here the structure of a minicircle population based on transcriptome sequencing of Leptomonas pyrrhocoris. We show that minicircle DNA molecules are dimeric. As in dixenous species, the entire molecule of minicircle DNA is transcribed. This is the first minicircle transcriptome of monoxenous trypanosomatid species determined using NGS technology.
May 2017: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/28595622/the-evolution-of-trypanosomatid-taxonomy
#5
REVIEW
Alexa Kaufer, John Ellis, Damien Stark, Joel Barratt
Trypanosomatids are protozoan parasites of the class Kinetoplastida predominately restricted to invertebrate hosts (i.e. possess a monoxenous life-cycle). However, several genera are pathogenic to humans, animals and plants, and have an invertebrate vector that facilitates their transmission (i.e. possess a dixenous life-cycle). Phytomonas is one dixenous genus that includes several plant pathogens transmitted by phytophagous insects. Trypanosoma and Leishmania are dixenous genera that infect vertebrates, including humans, and are transmitted by hematophagous invertebrates...
June 8, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28591312/identification-of-a-type-i-nitroreductase-gene-in-non-virulent-trypanosoma-rangeli
#6
Marjorie Montenegro, Claudia Cuervo, Constanza Cardenas, Silvia Duarte, Jenny R Díaz, M Carmen Thomas, Manuel C Lopez, Concepcion J Puerta
Trypanosomatid type I nitroreductases (NTRs), i.e., mitochondrial enzymes that metabolise nitroaromatic pro-drugs, are essential for parasite growth, infection, and survival. Here, a type I NTR of non-virulent protozoan Trypanosoma rangeli is described and compared to those of other trypanosomatids. The NTR gene was isolated from KP1(+) and KP1(-) strains, and its corresponding transcript and 5' untranslated region (5'UTR) were determined. Bioinformatics analyses and nitro-drug activation assays were also performed...
July 2017: Memórias do Instituto Oswaldo Cruz
https://www.readbyqxmd.com/read/28590590/repurposing-of-human-kinase-inhibitors-in-neglected-protozoan-diseases
#7
Maria Dichiara, Agostino Marrazzo, Orazio Prezzavento, Simona Collina, Antonio Rescifina, Emanuele Amata
Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, belong to a group of infectious diseases defined as neglected tropical diseases, induced by infection with protozoan parasites named trypanosomatids. Current drugs present several issues and the development of new candidates appears to be needed. The majority of the current therapeutic trypanosomatid targets are represented by enzymes or cell surface receptors. Among these, eukaryotic protein kinases represent a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases...
June 7, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28587841/3-nucleotidase-nuclease-in-protozoan-parasites-molecular-and-biochemical-properties-and-physiological-roles
#8
Anita Leocadio Freitas-Mesquita, José Roberto Meyer-Fernandes
3'-nucleotidase/nuclease (3'NT/NU) is a bi-functional enzyme that is able to hydrolyze 3'-monophosphorylated nucleotides and nucleic acids. This review summarizes the major molecular and biochemical properties of this enzyme in different trypanosomatid species. Sequence analysis of the gene encoding 3'NT/NU in Leishmania and Crithidia species showed that the protein possesses five highly conserved regions that are characteristic of members of the class I nuclease family. 3'NT/NU presents a molecular weight of approximately 40 kDa, which is conserved among the studied species...
June 3, 2017: Experimental Parasitology
https://www.readbyqxmd.com/read/28579611/anti-trypanosomatid-drug-discovery-an-ongoing-challenge-and-a-continuing-need
#9
Mark C Field, David Horn, Alan H Fairlamb, Michael A J Ferguson, David W Gray, Kevin D Read, Manu De Rycker, Leah S Torrie, Paul G Wyatt, Susan Wyllie, Ian H Gilbert
No abstract text is available yet for this article.
July 2017: Nature Reviews. Microbiology
https://www.readbyqxmd.com/read/28579388/targeting-cysteine-proteases-in-trypanosomatid-disease-drug-discovery
#10
REVIEW
Leonardo G Ferreira, Adriano D Andricopulo
Chagas disease and human African trypanosomiasis are endemic conditions in Latin America and Africa, respectively, for which no effective and safe therapy is available. Efforts in drug discovery have focused on several enzymes from these protozoans, among which cysteine proteases have been validated as molecular targets for pharmacological intervention. These enzymes are expressed during the entire life cycle of trypanosomatid parasites and are essential to many biological processes, including infectivity to the human host...
June 1, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28573456/backbone-nmr-assignments-of-tryparedoxin-the-central-protein-in-the-hydroperoxide-detoxification-cascade-of-african-trypanosomes-in-the-oxidized-and-reduced-form
#11
Annika Wagner, Erika Diehl, R Luise Krauth-Siegel, Ute A Hellmich
Tryparedoxin (Tpx) is a pivotal protein in the redox-metabolism of trypanosomatid parasites. Tpx has previously been identified as a potential target for drug development in the fight against human African sleeping sickness caused by Trypanosoma brucei. Tpx belongs to the thioredoxin superfamily and acts as an oxidoreductase in the parasite's cytoplasm. It contains a WCPPC active site motif, which enables the protein to undergo thiol-disulfide exchange. To promote future protein-drug interaction analyses, we report the (1)H, (13)C and (15)N backbone chemical shift assignments for both the oxidized and reduced states of Tpx...
June 1, 2017: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/28551817/discovery-of-novel-inhibitors-for-leishmania-nucleoside-diphosphatase-kinase-ndk-based-on-its-structural-and-functional-characterization
#12
Arjun K Mishra, Nidhi Singh, Pragati Agnihotri, Shikha Mishra, Saurabh P Singh, Bala K Kolli, Kwang Poo Chang, Amogh A Sahasrabuddhe, M I Siddiqi, J Venkatesh Pratap
Nucleoside diphosphate kinases (NDKs) are ubiquitous enzymes that catalyze the transfer of the γ-phosphate moiety from an NTP donor to an NDP acceptor, crucial for maintaining the cellular level of nucleoside triphosphates (NTPs). The inability of trypanosomatids to synthesize purines de novo and their dependence on the salvage pathway makes NDK an attractive target to develop drugs for the diseases they cause. Here we report the discovery of novel inhibitors for Leishmania NDK based on the structural and functional characterization of purified recombinant NDK from Leishmania amazonensis...
May 27, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28550086/the-iron-dependent-mitochondrial-superoxide-dismutase-soda-promotes-leishmania-virulence
#13
Bidyottam Mittra, Maria Fernanda Laranjeira-Silva, Danilo Ciccone Miguel, Juliana Perrone Bezerra de Menezes, Norma W Andrews
Leishmaniasis is one of the leading global neglected diseases, affecting millions of people worldwide. Leishmania infection depends on the ability of insect-transmitted metacyclic promastigotes to invade mammalian hosts, differentiate into amastigotes and replicate inside macrophages. To counter the hostile oxidative environment inside macrophages, these protozoans contain anti-oxidant systems that include iron-dependent superoxide dismutases (SODs) in mitochondria and glycosomes. Increasing evidence suggests that in addition to this protective role, Leishmania mitochondrial SOD may also initiate H2O2-mediated redox signaling that regulates gene expression and metabolic changes associated with differentiation into virulent forms...
May 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28503378/pollen-extracts-and-constituent-sugars-increase-growth-of-a-trypanosomatid-parasite-of-bumble-bees
#14
Evan C Palmer-Young, Lucy Thursfield
Phytochemicals produced by plants, including at flowers, function in protection against plant diseases, and have a long history of use against trypanosomatid infection. Floral nectar and pollen, the sole food sources for many species of insect pollinators, contain phytochemicals that have been shown to reduce trypanosomatid infection in bumble and honey bees when fed as isolated compounds. Nectar and pollen, however, consist of phytochemical mixtures, which can have greater antimicrobial activity than do single compounds...
2017: PeerJ
https://www.readbyqxmd.com/read/28499874/pyrrole-indolinone-su11652-targets-the-nucleoside-diphosphate-kinase-from-leishmania-parasites
#15
Plínio Salmazo Vieira, Tatiana de Arruda Campos Brasil Souza, Rodrigo Vargas Honorato, Letícia Maria Zanphorlin, Kelven Ulisses Severiano, Silvana Aparecida Rocco, Arthur Henrique Cavalcante de Oliveira, Artur Torres Cordeiro, Paulo Sérgio Lopes Oliveira, Priscila Oliveira de Giuseppe, Mário Tyago Murakami
Nucleoside diphosphate kinases (NDKs) are key enzymes in the purine-salvage pathway of trypanosomatids and have been associated with the maintenance of host-cell integrity for the benefit of the parasite, being potential targets for rational drug discovery and design. The NDK from Leishmania major (LmNDK) and mutants were expressed and purified to homogeneity. Thermal shift assays were employed to identify potential inhibitors for LmNDK. Calorimetric experiments, site-directed mutagenesis and molecular docking analysis were performed to validate the interaction and to evaluate the structural basis of ligand recognition...
May 9, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28499405/a-comparative-molecular-and-3-dimensional-structural-investigation-into-cross-continental-and-novel-avian-trypanosoma-spp-in-australia
#16
Crystal Cooper, R C Andrew Thompson, Adriana Botero, Amanda Kristancic, Christopher Peacock, Yaowanuj Kirilak, Peta L Clode
BACKGROUND: Molecular and structural information on avian Trypanosoma spp. throughout Australia is limited despite their intrinsic value in understanding trypanosomatid evolution, diversity, and structural biology. In Western Australia tissue samples (n = 429) extracted from 93 birds in 25 bird species were screened using generic PCR primers to investigate the diversity of Trypanosoma spp. To investigate avian trypanosome structural biology the first 3-dimensional ultrastructural models of a Trypanosoma spp...
May 12, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28486547/hat2-mediates-histone-h4k4-acetylation-and-affects-micrococcal-nuclease-sensitivity-of-chromatin-in-leishmania-donovani
#17
Pravin K Jha, Mohd Imran Khan, Anshul Mishra, Pradeep Das, Kislay K Sinha
Histone post-translational modifications (PTMs) such as acetylation and methylation are known to affect chromatin higher order structures. Primary targets of these modifications include basic residues present at N-terminus tail region of core histones. Four histone acetyltransferase (HAT) genes have been identified in trypanosomatids. HAT1, HAT3 and HAT4 of Leishmania donovani have been partially characterized. However, there is no report about HAT2 of Leishmania donovani. Lysine residues present on the N-terminal tail of Leishmania donovani histone H4 are conserved in other trypanosomatids and humans...
2017: PloS One
https://www.readbyqxmd.com/read/28483460/voacamine-alters-leishmania-ultrastructure-and-kills-parasite-by-poisoning-unusual-bi-subunit-topoisomerase-ib
#18
Somenath Roy Chowdhury, Ashish Kumar, Joseane Lima Prado Godinho, Sara Teixeira De Macedo Silva, Aline Araujo Zuma, Sourav Saha, Neha Kumari, Juliany Cola Fernandez Rodrigues, Shyam Sundar, Jean-Claude Dujardin, Syamal Roy, Wanderley De Souza, Sibabrata Mukhopadhyay, Hemanta K Majumder
Indole alkaloids possess a large spectrum of biological activities including anti-protozoal action. Here we report for the first time that voacamine, isolated from the plant Tabernaemontana coronaria, is an antiprotozoal agent effective against a large array of trypanosomatid parasites including Indian strain of Leishmania donovani and Brazilian strains of Leishmania amazonensis and Trypanosoma cruzi. It inhibits the relaxation activity of topoisomerase IB of L. donovani (LdTop1B) and stabilizes the cleavable complex...
May 5, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28472338/occurrence-and-probability-maps-of-lutzomyia-longipalpis-and-lutzomyia-cruzi-diptera-psychodidae-phlebotominae-in-brazil
#19
J D Andrade-Filho, R G C Scholte, A L G Amaral, P H F Shimabukuro, O S Carvalho, R L Caldeira
Leishmaniases are serious diseases caused by trypanosomatid protozoans of the genus Leishmania transmitted by the bite of phlebotomine sand flies. We analyzed records pertaining to Lutzomyia longipalpis (Lutz and Neiva, 1912) and Lutzomyia cruzi (Mangabeira, 1938) in Brazil from the following sources: the collection of phlebotomine sand flies of the Centro de Pesquisas René Rachou/Fiocruz (FIOCRUZ-COLFLEB), the "SpeciesLink" (CRIA) database, from systematic surveys of scientific articles and gray literature (dissertations, theses, and communications), and disease data obtained from the Information System for Notifiable Diseases/Ministry of Health (SINAN/MS)...
May 4, 2017: Journal of Medical Entomology
https://www.readbyqxmd.com/read/28465349/genetic-metabolic-complementation-establishes-a-requirement-for-gdp-fucose-in-leishmania
#20
Hongjie Guo, Natalia M Novozhilova, Giulia Bandini, Salvatore J Turco, Michael A J Ferguson, Stephen M Beverley
To survive in its sand fly vector, the trypanosomatid protozoan parasite Leishmania first attaches to the midgut to avoid excretion, but eventually it must detach for transmission by the next bite. In Leishmania major strain Friedlin, this is controlled by modifications of the stage-specific adhesin lipophosphoglycan (LPG). During differentiation to infective metacyclics, D-arabinopyranose (D-Arap) caps the LPG side-chain galactose residues, blocking interaction with the midgut lectin PpGalec, thereby leading to parasite detachment and transmission...
May 2, 2017: Journal of Biological Chemistry
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