scholarly journals Ivermectin inhibits extracellular vesicle secretion from parasitic nematodes

2020 ◽  
Author(s):  
Hannah J. Loghry ◽  
Wang Yuan ◽  
Mostafa Zamanian ◽  
Nicolas J. Wheeler ◽  
Timothy A. Day ◽  
...  
Keyword(s):  
Protein Secretion ◽  
Mode Of Action ◽  
Specific Property ◽  
Essential Medicine ◽  
Extracellular Vesicle ◽  
Parasitic Nematodes ◽  
Inhibitory Effects ◽  
Filarial Nematodes ◽  
Parasite Motility ◽  
Novel Drug

AbstractLymphatic filariasis (LF) is a disease caused by parasitic filarial nematodes that is endemic in 49 countries and affects or threatens over 890 million people. Strategies to control LF rely heavily on mass administration of anthelmintic drugs including ivermectin (IVM), a macrocyclic lactone drug considered an Essential Medicine by the WHO. However, despite its widespread use the therapeutic mode of action of IVM against filarial nematodes is not clear. We have previously reported that filarial nematodes secrete extracellular vesicles (EVs) and that their cargo has immunomodulatory properties. Here we investigate the effects of IVM and other anti-filarial drugs on parasitic nematode EV secretion, motility, and protein secretion. We show that inhibition of EV secretion was a specific property of IVM, which had consistent and significant inhibitory effects across nematode life stages and species (with the exception of male parasites). IVM inhibited EV secretion, but not parasite motility, at therapeutically relevant concentrations. Protein secretion was inhibited by IVM in the microfilariae stage, but not in any other stage tested. Our data provides evidence that inhibiting the secretion of immunomodulatory EVs by parasitic nematodes could explain, at least in part, IVM mode of action and provides a phenotype for novel drug discovery.

scholarly journals Natural variation in Caenorhabditis elegans responses to the anthelmintic emodepside

2021 ◽  
Author(s):  
Janneke Wit ◽  
Steffen R. Hahnel ◽  
Briana C. Rodriguez ◽  
Erik Andersen
Keyword(s):  
Caenorhabditis Elegans ◽  
Mode Of Action ◽  
Natural Variation ◽  
Treatment Strategies ◽  
Parasitic Nematodes ◽  
Anthelmintic Drug ◽  
C Elegans ◽  
Hormetic Effect ◽  
Filarial Nematodes

Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adapted Caenorhabditis elegans strain N2 is sensitive to emodepside, and genetic selection and in vitro experiments implicated slo-1, a BK potassium channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wild C. elegans strains after exposure to the drug and found natural variation across the species. Some variation in emodepside responses can be explained by natural differences in slo-1. This result suggests that other genes in addition to slo-1 underlie emodepside resistance in wild C. elegans strains. Additionally, all assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect), which could impact treatment strategies. We find that natural variation affects emodepside sensitivity, supporting the suitability of C. elegans as a model system to study emodepside responses across parasitic nematodes.

scholarly journals 4E Interacting Protein as a Potential Novel Drug Target for Nucleoside Analogues in Trypanosoma Brucei

2021 ◽  
Vol 9 (4) ◽  
pp. 826
Author(s):  
Dorien Mabille ◽  
Camila Cardoso Santos ◽  
Rik Hendrickx ◽  
Mathieu Claes ◽  
Peter Takac ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Drug Target ◽  
Drug Targets ◽  
De Novo ◽  
Treatment Options ◽  
Adenosine Kinase ◽  
Nucleoside Analogues ◽  
Purine Salvage ◽  
Interacting Protein ◽  
Novel Drug

Human African trypanosomiasis is a neglected parasitic disease for which the current treatment options are quite limited. Trypanosomes are not able to synthesize purines de novo and thus solely depend on purine salvage from the host environment. This characteristic makes players of the purine salvage pathway putative drug targets. The activity of known nucleoside analogues such as tubercidin and cordycepin led to the development of a series of C7-substituted nucleoside analogues. Here, we use RNA interference (RNAi) libraries to gain insight into the mode-of-action of these novel nucleoside analogues. Whole-genome RNAi screening revealed the involvement of adenosine kinase and 4E interacting protein into the mode-of-action of certain antitrypanosomal nucleoside analogues. Using RNAi lines and gene-deficient parasites, 4E interacting protein was found to be essential for parasite growth and infectivity in the vertebrate host. The essential nature of this gene product and involvement in the activity of certain nucleoside analogues indicates that it represents a potential novel drug target.

scholarly journals Aberrant astrocyte protein secretion contributes to altered neuronal development in diverse disorders

2020 ◽  
Author(s):  
Alison L.M. Caldwell ◽  
Jolene K. Diedrich ◽  
Maxim N. Shokhirev ◽  
Nicola J. Allen
Keyword(s):  
Protein Secretion ◽  
Neuronal Development ◽  
Fragile X ◽  
Gene Expression Change ◽  
Bmp Signaling ◽  
Inhibitory Effects ◽  
Expression Change ◽  
In Vitro System ◽  
Novel Targets

AbstractAstrocytes negatively impact neuronal development in many neurodevelopmental disorders (NDs), however how they do this, and if mechanisms are shared across disorders, is not known. We developed an in vitro system to ask how astrocyte protein secretion and gene expression change in three genetic NDs. We identified disorder specific changes, and changes common to all disorders. ND astrocytes increase release of Igfbp2, a secreted inhibitor of IGF. IGF rescues neuronal deficits in many NDs, and we found blocking Igfbp2 partially rescues inhibitory effects of Rett Syndrome astrocytes, suggesting increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified increased BMP signaling in ND astrocytes is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X Syndrome astrocytes reverses inhibitory effects on neurite outgrowth. We provide a resource of astrocyte secreted proteins in health and NDs, and identify novel targets for intervention in diverse NDs.

scholarly journals Marigolds (Tagetes spp.) for Nematode Management

EDIS ◽  
2007 ◽  
Vol 2007 (19) ◽  
Author(s):  
R. Krueger ◽  
K. E. Dover ◽  
Robert McSorley ◽  
K. H. Wang
Keyword(s):  
Mode Of Action ◽  
Cover Crop ◽  
Parasitic Nematodes ◽  
Plant Parasitic Nematodes ◽  
Root Knot Nematodes ◽  
Fact Sheet ◽  
Nematode Management ◽  
Plant Parasitic

ENY-056, an 8-page fact sheet by R. Krueger, K. E. Dover, R. McSorley, and K. -H. Wang, introduces homeowners to the problem of root-knot nematodes, the use of marigolds as an allelopathic cover crop for nematode suppression. It describes the mode of action, planting tips, considerations, and frequently asked questions. Includes references and tables showing susceptibility of marigold varieties to root-knot and plant-parasitic nematodes in Florida. Published by the UF Department of Entomology and Nematology, August 2007. ENY-056/NG045: Marigolds (Tagetes spp.) for Nematode Management (ufl.edu)

scholarly journals Development of Antibody–Oligonucleotide Complexes for Targeting Exosomal MicroRNA

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 545 ◽  
Author(s):  
Asako Yamayoshi ◽  
Shota Oyama ◽  
Yusuke Kishimoto ◽  
Ryo Konishi ◽  
Tsuyoshi Yamamoto ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Inhibitory Effects ◽  
Exosomal Mirnas ◽  
Functional Inhibition ◽  
Novel Drug Delivery System ◽  
Exosomal Mirna ◽  
Novel Drug ◽  
Exosomal Microrna

MicroRNAs in exosomes (exosomal miRNAs) are considered as significant targets for cancer therapy. Anti-miR oligonucleotides are often used for the functional inhibition of miRNAs; however, there are no studies regarding the regulation of exosomal miRNA functions. In this study, we attempted to develop a novel drug delivery system using anti-exosome antibody–anti-miR oligonucleotide complexes (ExomiR-Tracker) to hijack exosomes to carry anti-miR oligonucleotides inside exosome-recipient cells. We found that ExomiR-Tracker bound to the exosomes, and then the complexes were introduced into the recipient cells. We also found that anti-miR oligonucleotides introduced into the recipient cells can exhibit inhibitory effects on exosomal miRNA functions in vitro and in vivo. We believe that our strategy would be a promising one for targeting exosomal miRNAs.

scholarly journals Serine/threonine phosphatases in socioeconomically important parasitic nematodes—Prospects as novel drug targets?

2011 ◽  
Vol 29 (1) ◽  
pp. 28-39 ◽  
Author(s):  
Bronwyn E. Campbell ◽  
Andreas Hofmann ◽  
Adam McCluskey ◽  
Robin B. Gasser
Keyword(s):  
Drug Targets ◽  
Parasitic Nematodes ◽  
Novel Drug ◽  
Novel Drug Targets

scholarly journals The effect of flavomycin on the synthesis and transfer of lipid-linked saccharides in pig brain

1982 ◽  
Vol 201 (3) ◽  
pp. 481-487 ◽  
Author(s):  
Ernst Bause ◽  
Günter Legler
Keyword(s):  
Mode Of Action ◽  
Direct Interaction ◽  
Inhibitory Effects ◽  
Dolichyl Phosphate ◽  
Pig Brain ◽  
Endogenous Protein ◽  
High Concentrations ◽  
Sugar Derivatives ◽  
Competitive Nature ◽  
Derivatives Of

Particulate membrane fractions from pig brain catalyse the synthesis of lipid-linked sugar derivatives of the dolichyl phosphate pathway. Flavomycin, a phosphoglycolipid antibiotic produced by various species of streptomycetes, interferes with the formation of these glycolipids to a different extent. The formation of dolichyl phosphate glucose was shown to be most susceptible to the antibiotic, being blocked by about 50% in the presence of 0.2mm-flavomycin, whereas the synthesis of dolichyl diphosphate N-acetylglucosamine, dolichyl diphosphate chitobiose and dolichyl diphosphate chitobiosyl mannose required higher concentrations to achieve a comparable inhibition. Although the formation of dolichyl phosphate mannose was hardly affected, the accumulation of oligosaccharides with five to seven sugar units was observed, when dolichyl diphosphate oligosaccharides were synthesized with GDP-[14C]mannose in the presence of 1mm-flavomycin. This indicates that the inhibition of the synthesis of larger-sized oligosaccharides, known to be mediated by lipid-bound mannose, was not caused by an actual deficiency in dolichyl phosphate mannose. At flavomycin concentrations that inhibited the formation of dolichyl phosphate glucose by 50%, the transfer of lipid-linked saccharides to either the hexapeptide Tyr-Asn-Gly-Thr-Ser-Val or endogenous protein acceptors was hardly influenced. The mode of action of flavomycin is still obscure, but seems not to be of a competitive nature, since the inhibition was unaffected by increasing concentrations of dolichyl phosphate. Some evidence indicates that, besides a direct interaction of the antibiotic with some transferases, a non-specific incorporation into the membrane and alteration of its properties might be responsible for those inhibitory effects on all enzymes which were observed at high concentrations of flavomycin.

Cardiac-inhibiting properties of the sesquiterpene lactone, parthenin, in the migratory grasshopper, Melanoplus sanguinipes

1981 ◽  
Vol 59 (2) ◽  
pp. 285-292 ◽  
Author(s):  
Anna K. Picman ◽  
R. H. Elliott ◽  
G. H. N. Towers
Keyword(s):  
Glutamic Acid ◽  
Plant Defense ◽  
Sesquiterpene Lactone ◽  
Mode Of Action ◽  
Reduced Glutathione ◽  
Sesquiterpene Lactones ◽  
Melanoplus Sanguinipes ◽  
Inhibitory Effects ◽  
Lethal Effects ◽  
Sulphydryl Groups

The cardiac-inhibiting properties of the sesquiterpene lactone, parthenin, were examined on semiisolated heart preparations of the migratory grasshopper, Melanoplus sanguinipes. Compared with saline-treated hearts, 0.3 mM parthenin significantly increased the frequency of heartbeat. However, higher concentrations of parthenin (3.4–51.3 mM) were progressively more inhibitory and caused a cessation in heartbeat within 1 h after application.Parthenin-arrested hearts treated with reduced glutathione, DL-cystathionine, acetylcholine, or L-glutamic acid remained inactive. In contrast, L-cysteine, DL-homocysteine, or dithiothreitol (DTT) reinitiated heartbeat in parthenin-arrested hearts. When the isolated monoadduct of parthenin and cysteine was applied to heart preparations, no inhibitory effects were apparent. The inhibitory effects of parthenin could also be delayed or prevented by mixing the compound with equimolar concentrations of cysteine, homocysteine, or DTT prior to its application to the heart. Because certain thiol agents negate or neutralize the cardiac-inhibiting properties of parthenin, the findings suggest that the lethal effects of sesquiterpene lactones on insects are due, in part, to an interference with free sulphydryl groups which appear essential to normal cardiac activity.The implications of these findings are discussed in terms of the mode of action, detoxification, and importance of parthenin in plant defense.

scholarly journals Synthesis and anti-tubercular activity of 3-substituted benzothiophene-1,1-dioxides

2014 ◽  
Author(s):  
N. Susantha Chandrasekera ◽  
Mai A Bailey ◽  
Megan Files ◽  
Torey Alling ◽  
Stephanie K Florio ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Minimum Inhibitory Concentration ◽  
Mode Of Action ◽  
Drug Targets ◽  
Inhibitory Concentration ◽  
Eukaryotic Cells ◽  
Structure Activity ◽  
Novel Drug ◽  
Further Development ◽  
Novel Drug Targets

We demonstrated that the 3-substituted benzothiophene-1,1-dioxide class of compounds are effective inhibitors of Mycobacterium tuberculosis growth under aerobic conditions. We examined substitution at the C-3 position of the benzothiophene-1,1-dioxide series systematically to delineate structure-activity relationships influencing potency and cytotoxicity. Compounds were tested for inhibitory activity against virulent M. tuberculosis and eukaryotic cells. The tetrazole substituent was most potent, with a minimum inhibitory concentration (MIC) of 2.6 µM. However, cytotoxicity was noted with even more potency (Vero cell TC50 = 0.1 µM). Oxadiazoles had good anti-tubercular activity (MICs of 3–8 µM), but imidazoles, thiadiazoles and thiazoles had little activity. Cytotoxicity did not track with anti-tubercular activity, suggesting different targets or mode of action between bacterial and eukaryotic cells. However, we were unable to derive analogs without cytotoxicity; all compounds synthesized were cytotoxic (TC50 of 0.1–5 µM). We conclude that cytotoxicity is a liability in this series precluding it from further development. However, the series has potent anti-tubercular activity and future efforts towards identifying the mode of action could result in the identification of novel drug targets.

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