Targeting the nervous system of the parasitic worm, Haemonchus contortus, with quercetin.

High Prevalence of infection rate, limited choice of drugs, and emerging resistance against these leads to a pressing need for the development of new antihelminthic drugs and drug targets. However, limited understanding of the physiology of worms has delayed the process substantially. Here, for the first time, we are reporting the tissue morphology of Haemonchus contortus, and target its nervous system with quercetin, a naturally occurring flavonoid. Quercetin showed anthelmintic activity against all developmental stages of the nematode. Histological analysis demonstrated damage of various body parts including isthmus, brut, pseudocoele, and other organs. Mechanistic studies revealed the generation of oxidative stress and alteration of the stress response enzyme activities. Importantly, the time-dependent imaging of ROS generation revealed the neuronal system as the primary target of quercetin in adult worms, which eventually leads to the paralysis and death of the worms. This work demonstrates the neuronal system as a novel drug target for quercetin.

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Targeting the Nervous System of the Parasitic Worm, Haemonchus Contortus, With Quercetin.

10.21203/rs.3.rs-887726/v1 ◽

2021 ◽

Author(s):

Vanshita Goel ◽

Neloy Chakroborty ◽

Sunidhi Sharma ◽

Lachhman Singla ◽

Diptiman Choudhury

Keyword(s):

Nervous System ◽

Haemonchus Contortus ◽

Drug Targets ◽

Developmental Stages ◽

Anthelmintic Activity ◽

Ros Generation ◽

Body Parts ◽

Parasitic Worm ◽

Flavonoid Quercetin ◽

Novel Target

Abstract Prevalence of infection, limited choice of drugs, and emerging resistance against contemporary drugs lead to a pressing need to develop new anthelmintic drugs and drug targets. However, limited understanding of the physiology of worms has delayed the process substantially. Here, for the first time, we are reporting the tissue morphology of Haemonchus contortus and targeting its nervous system with quercetin, a naturally occurring flavonoid. Quercetin showed anthelmintic activity against all of the developmental stages of the H. contortus. Further, histological analysis demonstrated damage of various body parts, including isthmus, brut, pseudocoele, and other organs due to quercetin treatment. Mechanistic studies revealed the generation of oxidative stress and alterations in activities of the stress response enzymes, such as catalase, superoxide dismutase, and glutathione peroxidase. Moreover, the time-dependent imaging of ROS-generation disclosed neuropils as the primary targets of quercetin in the adult worms, which eventually lead to the paralysis and death of the worms. Thus, altogether, this work demonstrates that the nervous system of the parasitic helminth, H. contortus, is a novel target of the drug quercetin.

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Author response: Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

10.7554/elife.51850.sa2 ◽

2019 ◽

Author(s):

David M Curran ◽

Alexandra Grote ◽

Nirvana Nursimulu ◽

Adam Geber ◽

Dennis Voronin ◽

...

Keyword(s):

Drug Targets ◽

Author Response ◽

Bacterial Endosymbiont ◽

Parasitic Worm ◽

Response Modeling ◽

Novel Drug ◽

Novel Drug Targets

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Decision letter: Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

10.7554/elife.51850.sa1 ◽

2019 ◽

Author(s):

Nicola L Harris ◽

James B Lok

Keyword(s):

Drug Targets ◽

Bacterial Endosymbiont ◽

Parasitic Worm ◽

Novel Drug ◽

Novel Drug Targets

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A Nanoinformatics Approach to Evaluate the Pharmacological Properties of Nanoparticles for the treatment of Alzheimer’s Disease

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210217145733 ◽

2021 ◽

Vol 24 ◽

Author(s):

Muhammad Zohaib Nawaz ◽

Syed Awais Attique ◽

Qurat-ul-Ain ◽

Fahdah Ayed Alshammari ◽

Heba Waheeb Alhamdi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Carbon Nanotubes ◽

Alzheimer's Disease ◽

Nervous System ◽

Drug Targets ◽

Kinase Domain ◽

New Drugs ◽

Drug Candidates ◽

Experimental Approaches ◽

Novel Drug

Background: Alzheimer’s disease is a nervous system destructive disease which causes structural, biochemical and electrical abnormalities inside the human brain and results due to genetic and various environmental factors. Traditional therapeutic agents of Alzheimer’s disease such as tacrine and physostigmine has been found causing adverse effects to the nervous system and gastrointestinal tract. Nanomaterials like graphene, metals, carbon-nanotubes and metal-oxides are gaining attention as potential drugs against Alzheimer’s disease due to their properties such as large surface area which provides clinical efficiency, targeted drug designing and delivery. Objectives: Designing new drugs by using experimental approaches are time-consuming, tedious and laborious processes which also require advanced technologies. This study aims to identify the novel drug candidates against Alzheimer’s disease with no or less associated side effects using molecular docking approaches. Methods: In this study, we utilized nanoinformatics based approaches for evaluating the interaction properties of various nanomaterials and metal nanoparticles with the drug targets including TRKB kinase domain, EphA4 and histone deacetylase. Furthermore, drug-likeness of carbon nanotubes was confirmed through ADME analysis. Results: Carbon nanotubes, either single or double-walled in all the three-configuration including zigzag, chiral, and armchair forms are found to interact with the target receptors with varying affinities. Conclusion: This study provides a novel and clearer insights into the interaction properties and drug suitability of known putative nanoparticles as potential agents for the treatment of Alzheimer’s disease.

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Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

eLife ◽

10.7554/elife.51850 ◽

2020 ◽

Vol 9 ◽

Author(s):

David M Curran ◽

Alexandra Grote ◽

Nirvana Nursimulu ◽

Adam Geber ◽

Dennis Voronin ◽

...

Keyword(s):

Drug Targets ◽

Metabolic Networks ◽

Metabolic Model ◽

Endosymbiotic Bacteria ◽

Parasitic Worm ◽

Eukaryotic Organisms ◽

New Treatments ◽

Genome Scale ◽

Novel Drug ◽

Novel Drug Targets

The filarial nematode Brugia malayi represents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteria Wolbachia—present in many filariae—which is vital to the worm. Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but have only been applied to multicellular eukaryotic organisms more recently. Here, we present iDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 102 reactions essential to the survival of B. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.

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Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

10.1101/767798 ◽

2019 ◽

Author(s):

DM Curran ◽

A Grote ◽

N Nursimulu ◽

A Geber ◽

D Voronin ◽

...

Keyword(s):

Drug Targets ◽

Metabolic Networks ◽

Metabolic Model ◽

Endosymbiotic Bacteria ◽

Parasitic Worm ◽

Eukaryotic Organisms ◽

New Treatments ◽

Genome Scale ◽

Novel Drug ◽

Novel Drug Targets

AbstractThe filarial nematodeBrugia malayirepresents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteriaWolbachia—present in many filariae—which is vital to the worm.Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but only recently have been applied to eukaryotic organisms. Here, we presentiDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 99 reactions essential to the survival ofB. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.

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