scholarly journals Genomewide Analysis of Mode of Action of the S-Adenosylmethionine Analogue Sinefungin in Leishmania infantum

mSystems ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Arijit Bhattacharya ◽  
Mansi Sharma ◽  
Charles Packianathan ◽  
Barry P. Rosen ◽  
Philippe Leprohon ◽  
...  
Keyword(s):  
Drug Targets ◽  
Protozoan Parasite ◽  
Cell Types ◽  
Biosynthetic Pathways ◽  
Potential Drug ◽  
Pathogenic Parasite ◽  
Potential Drug Targets ◽  
Chemotherapeutic Interventions

The two main cellular metabolic one-carbon donors are reduced folates and S-adenosylmethionine, whose biosynthetic pathways have proven highly effective in chemotherapeutic interventions in various cell types. Sinefungin, a nucleoside analogue of S-adenosylmethionine, was shown to have potent activity against the protozoan parasite Leishmania. Here, we studied resistance to sinefungin using whole-genome approaches as a way to further our understanding of the role of S-adenosylmethionine in this parasite and to reveal novel potential drug targets. These approaches allowed the characterization of novel features related to S-adenosylmethionine function in Leishmania which could further help in the development of sinefungin-like compounds against this pathogenic parasite.

Structure, Function and Interactions of Tau: Particular Focus on Potential Drug Targets for the Treatment of Tauopathies

2018 ◽  
Vol 17 (5) ◽  
pp. 325-337 ◽  
Author(s):  
Hojjat Borna ◽  
Kasim Assadoulahei ◽  
Gholamhossein Riazi ◽  
Asghar Beigi Harchegani ◽  
Alireza Shahriary
Keyword(s):  
Tau Protein ◽  
Drug Targets ◽  
Brain Injuries ◽  
Potential Drug ◽  
Microtubule Network ◽  
Wide Range ◽  
Potential Risk Factors ◽  
Range Of Functions ◽  
Potential Drug Targets

Background & Objective: Neurodegenrative diseases are among the most widespread lifethreatening disorders around the world in elderly ages. The common feature of a group of neurodegenerative disorders, called tauopathies, is an accumulation of microtubule associated protein tau inside the neurons. The exact mechanism underlying tauopathies is not well-understood but several factors such as traumatic brain injuries and genetics are considered as potential risk factors. Although tau protein is well-known for its key role in stabilizing and organization of axonal microtubule network, it bears a broad range of functions including DNA protection and participation in signaling pathways. Moreover, the flexible unfolded structure of tau facilitates modification of tau by a wide range of intracellular enzymes which in turn broadens tau function and interaction spectrum. The distinctive properties of tau protein concomitant with the crucial role of tau interaction partners in the progression of neurodegeneration suggest tau and its binding partners as potential drug targets for the treatment of neurodegenerative diseases. Conclusion: This review aims to give a detailed description of structure, functions and interactions of tau protein in order to provide insight into potential therapeutic targets for treatment of tauopathies.

The transcriptome of Echinostoma caproni adults: Further characterization of the secretome and identification of new potential drug targets

2013 ◽  
Vol 89 ◽  
pp. 202-214 ◽  
Author(s):  
Gagan Garg ◽  
Dolores Bernal ◽  
Maria Trelis ◽  
Javier Forment ◽  
Javier Ortiz ◽  
...  
Keyword(s):  
Drug Targets ◽  
Potential Drug ◽  
Echinostoma Caproni ◽  
Potential Drug Targets

scholarly journals A small mitochondrial protein present in myzozoans is essential for malaria transmission

Open Biology ◽  
2016 ◽  
Vol 6 (4) ◽  
pp. 160034 ◽  
Author(s):  
Dennis Klug ◽  
Gunnar R. Mair ◽  
Friedrich Frischknecht ◽  
Ross G. Douglas
Keyword(s):  
Drug Targets ◽  
Mitochondrial Protein ◽  
Sister Group ◽  
Developmental Defect ◽  
Mitochondrial Mass ◽  
First Time ◽  
Potential Drug Targets ◽  
Identification And Characterization

Myzozoans (which include dinoflagellates, chromerids and apicomplexans) display notable divergence from their ciliate sister group, including a reduced mitochondrial genome and divergent metabolic processes. The factors contributing to these divergent processes are still poorly understood and could serve as potential drug targets in disease-causing protists. Here, we report the identification and characterization of a small mitochondrial protein from the rodent-infecting apicomplexan parasite Plasmodium berghei that is essential for development in its mosquito host. Parasites lacking the gene mitochondrial protein ookinete developmental defect ( mpodd ) showed malformed parasites that were unable to transmit to mosquitoes. Knockout parasites displayed reduced mitochondrial mass without affecting organelle integrity, indicating no role of the protein in mitochondrial biogenesis or morphology maintenance but a likely role in mitochondrial import or metabolism. Using genetic complementation experiments, we identified a previously unrecognized Plasmodium falciparum homologue that can rescue the mpodd(−) phenotype, thereby showing that the gene is functionally conserved. As far as can be detected, mpodd is found in myzozoans, has homologues in the phylum Apicomplexa and appears to have arisen in free-living dinoflagellates. This suggests that the MPODD protein has a conserved mitochondrial role that is important for myzozoans. While previous studies identified a number of essential proteins which are generally highly conserved evolutionarily, our study identifies, for the first time, a non-canonical protein fulfilling a crucial function in the mitochondrion during parasite transmission.

Abstract 4627: The role of human endogenous retroviral proteins in the development of Merlin-deficient tumors and as potential drug targets

2016 ◽  
Author(s):  
Emmanuel Maze ◽  
Shona Reeves ◽  
David Hilton ◽  
Lucy Provenzano ◽  
Robert Belshaw ◽  
...  
Keyword(s):  
Drug Targets ◽  
Potential Drug ◽  
Potential Drug Targets

scholarly journals Characterization of G-Quadruplex Motifs in espB, espK, and cyp51 Genes of Mycobacterium tuberculosis as Potential Drug Targets

2019 ◽  
Vol 16 ◽  
pp. 698-706 ◽  
Author(s):  
Subodh Kumar Mishra ◽  
Uma Shankar ◽  
Neha Jain ◽  
Kriti Sikri ◽  
Jaya Sivaswami Tyagi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Potential Drug ◽  
G Quadruplex ◽  
Potential Drug Targets

scholarly journals Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

2013 ◽  
Vol 57 (12) ◽  
pp. 5969-5976 ◽  
Author(s):  
Peter D. Ziniel ◽  
Janish Desai ◽  
Cynthia L. Cass ◽  
Craig Gatto ◽  
Eric Oldfield ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Drug Targets ◽  
Protein Characterization ◽  
Farnesyl Diphosphate ◽  
Farnesyl Diphosphate Synthase ◽  
Potential Drug ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate ◽  
Potential Drug Targets

ABSTRACTSchistosomiasis affects over 200 million people worldwide, with over 200,000 deaths annually. Currently, praziquantel is the only drug available against schistosomiasis. We report here thatSchistosoma mansonifarnesyl diphosphate synthase (SmFPPS) and geranylgeranyl diphosphate synthase (SmGGPPS) are potential drug targets for the treatment of schistosomiasis. We expressed active, recombinantSmFPPS andSmGGPPS for subsequent kinetic characterization and testing against a variety of bisphosphonate inhibitors. RecombinantSmFPPS was found to be a soluble 44.2-kDa protein, whileSmGGPPS was a soluble 38.3-kDa protein. Characterization of the substrate utilization of the two enzymes indicates that they have overlapping substrate specificities. AgainstSmFPPS, several bisphosphonates had 50% inhibitory concentrations (IC50s) in the low micromolar to nanomolar range; these inhibitors had significantly less activity againstSmGGPPS. Several lipophilic bisphosphonates were active againstex vivoadult worms, with worm death occurring over 4 to 6 days. These results indicate that FPPS and GGPPS could be of interest in the context of the emerging resistance to praziquantel in schistosomiasis therapy.

scholarly journals Characterization of highly conserved G-quadruplex motifs as potential drug targets in Streptococcus pneumoniae

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Subodh Kumar Mishra ◽  
Neha Jain ◽  
Uma Shankar ◽  
Arpita Tawani ◽  
Tarun Kumar Sharma ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Drug Targets ◽  
Potential Drug ◽  
G Quadruplex ◽  
Potential Drug Targets

scholarly journals Mefloquine interferes with glycolysis in schistosomula of Schistosoma mansoni via inhibition of enolase

Parasitology ◽  
2012 ◽  
Vol 139 (4) ◽  
pp. 497-505 ◽  
Author(s):  
THERESIA MANNECK ◽  
JENNIFER KEISER ◽  
JOACHIM MÜLLER
Keyword(s):  
Mass Spectrometry ◽  
Schistosoma Mansoni ◽  
Sodium Fluoride ◽  
Drug Targets ◽  
Potential Role ◽  
Glycolytic Enzyme ◽  
Potential Drug ◽  
Crude Extracts ◽  
Potential Drug Targets

SUMMARYThe antimalarial drug mefloquine has promising antischistosomal properties killing haematophagous adult schistosomes as well as schistosomula. The mode of action and involved drug targets of mefloquine in Schistosoma mansoni schistosomula are unknown. In order to identify mefloquine-binding proteins and thus potential drug targets, mefloquine affinity chromatography with S. mansoni schistosomula crude extracts was performed. We found one specific mefloquine-binding protein that was identified by mass spectrometry as the glycolytic enzyme enolase (Q27877). Enolase activity assays were performed on schistosomula crude extracts and on the recombinant enolase Q27877 expressed in Escherichia coli. In schistosomula crude extracts enolase activity was inhibited by mefloquine and by the enolase inhibitor sodium fluoride, while activity of the recombinant enolase was not affected. In contrast to enolase from crude extracts, recombinant Q27877 did not bind to mefloquine-agarose. Using isothermal microcalorimetry, we next investigated the metabolic inhibition of mefloquine and 3 known glycolytic inhibitors in Schistosoma spp., namely sodium fluoride, 3-bromopyruvate and menadione on schistosomula in the presence or absence of glucose. We found that in the presence of glucose, schistosomula were less affected by mefloquine, sodium fluoride and 3-bromopyruvate, whereas glucose had no protective effect when schistosomula had been exposed to menadione. These results suggest a potential role of mefloquine as an inhibitor of glycolysis, at least in stages where other targets like haem degradation are not relevant.

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