Anthelmintic drug: overview and traditional discovery approaches

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This ppt gives information about Anthelmintic drug in relation to plants, animals, & humans


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Anthelmintic Drugs: Overview And Traditional Discovery Approaches:

Anthelmintic Drugs: Overview And Traditional Discovery A pproaches Ashish Kumar Singh Division of Nematology IARI, New Delhi. Chairperson : Dr.Anil S irohi Seminar leader : Dr.Vishal S. Somvanshi 1

The Nematode Problems:

The Nematode Problems Zoonotic Potential 2 >2.2 billion people infected with nematodes USD 157 billion loss to agriculture caused by nematodes http://

Plant Parasites:

Plant Parasites Meloidogyne Heterodera Pratylenchus Rotylenchulus Globodera Aphelenchoides Ditylenchus Longidorus , Trichodorus Xiphinema S. Sardanelli 3

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Annual crop yield loss in US dollars (billion) by nematodes in 2001 based on 1987 international yield loss survey ( Sasser & Freckman , 1987 ). WORLDWIDE 5 -12% ANNUAL LOSSES DUE TO PLANT PARASITIC NEMATODES ( SASSER AND FRECKMAN, 1987

Human Parasites & Animal Parasites:

Human Parasites & Animal Parasites Human parasites Ascaris lumbricoides . Trichuris trichiura . Enterobius vermicularis Ancylostoma duodenale . Dracunculus medinensis Schistosoma Trichinella spiralis Wuchereia bancrofti Onchocerca volvulus Loa loa Animal parasites Ascaris   suum Trichinella   Dirofilaria immitis Toxocara canis Trichuris spp. Bunostomum trigonocephalum 5

How to Overcome These Problems???:

How to Overcome T hese P roblems??? 6


Anthelmintics Anthelmintics are drugs or molecules that are used to treat parasitic helminth infections such as nematodes. For e.g. albendazole, ivermectin, pyrantel Theoretically same molecule can be used against other group of nematodes such as plant parasites Drug vs. agricultural chemicals 7

Key Drugs Registered :

Key D rugs R egistered Schistosomiasis Intestinal roundworm Antimonials Piperazine Metifonate Benzimidazole Oxamaquine Morantel Praziquantel Pyrantel Cestodiasis Levamisole Niclosamide Avermectins Benzimidazole Closantel Priaziquantel Emodepside Fasciolasis Filariasis Praziquantel Diethylcarbmazine Closantel Suramin 8

Mode of action:

Targeted sites Nicotinic agonists Acetylcholinesterase inhibitors GABA agonist GluCI potentiators Calcium permeability increase Tubulin binding Proton ionophores Drugs Ievamlisole , pyrantel , monantel Haloxon Piperazine Ivermectin, abamectin Praziquintel , Thiabendazole , albendazole Niclosamide , Mode of action 9


Fumigants Chemical name Trade name Formulation Methyl bromide Dowfume Gas 1,3 dichloropropene Telone /DD-95 Liquid Ethelene dibromide Dowfume W-85 Liquid Metam sodium Vapam Liquid Dazomet Basamid Dust ( prill ) Methyl isothiocynate Di- trapex Liquid Chloropicrin Larvacide Liquid 10


Organophosphates Chemical name Trade name Formulation Thionazin Nemafos Granular or E.C. Ethoprophos Mocap Granular or E.C. Fenamiphos Nemacure Granular or E.C. Fensulfothian Dasanit Granular Terbufos Counter Granular Isazophos Miral Granular or E.C. Ebufos Rugby Granular or E.C. 11


Carbamates Chemical name Trade name Formulation Aldicarb Temik Granular Aldoxycarb Standak Flowable Oxamyl Vydate Granular or E.C. Carbafuran Furadan Granular or flowable Cleothiocarb Lance Granular 12

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How Are New Drugs Developed ???:

How Are N ew D rugs D eveloped ??? 14

The Drug Discovery Process :

The Drug D iscovery P rocess 15

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The D0 phase Choice of therapeutic areas and indication. Choice of therapeutic target. Cell membrane receptors and ion channels. Intra- or extracellular enzyme. Nuclear receptors. The D1 phase High-throughput screening for therapeutic tool. Low molecular weight compounds, synthetics. Low molecular weight molecules, natural products. Organisms botanicals 16

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The D2 phase High-throughput screening of public and proprietary compound libraries. L igand screening for hit identification. The D3 phase Lead optimization to investigate… Solubility, potency, selectivity, metabolic properties, as well as their side effect profile both in in vitro and in whole animal models. The D4 phase This phase is the final preparation for the clinical evaluation of a potential drug candidate. Ph I-IV Preclinical to clinical drug evaluation. 17

Approaches To Drug Discovery :

Approaches To D rug D iscovery Approaches for drug discovery 18

Short Term :

Short Term Combinations of existing drugs . Praziquante and oxamniquine for schistosomiasis New indications for existing drugs. Insecticides with nematicides property Improvements to known drugs and compound classes. Moxidectin lymphatic filariasis and onchocerciasis Focused sample collections . 19

Long Term :

Long Term 1. Target based : Start with a molecular target such as an enzyme, receptor, channel. Identify molecules that interact with target. Apply molecular and chemical knowledge to investigate specific molecular hypotheses. 2. Phenotypic screening : Start with a functional assay such as a cells, tissue or animal. M easure activity against a biomarker related to the disease. T he assays do not require prior understanding of underlying molecular mechanism of action (MMOA). Modified natural substances Biologics 20

Long Term :

Long Term Phenotypic screening: The main application of phenotypic assays is to screen large compound libraries. A lso called ‘forward pharmacology’, ‘classical pharmacology.’ Compounds are then screened in the phenotypic assay to identify active lead compounds that eliminate pathogens in culture. The phenotypic screen is usually more physiologically relevant and less artificial. Primary hits identified have multiple targets : proteins (receptors, enzymes, transcription factors) . signaling pathways. Lead compounds further selected from the hits with or without knowledge of the target. 21

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David C. Swinney & Jason Anthony 2012 22

Phenotypic Screenings:

Phenotypic Screenings Animal-based phenotypic screens. Cell-based phenotypic assays. 23

Animal-based phenotypic screens :

Many disease models of several small animals including Caenorhabditis elegans , used for compound screening in vivo. These models can provide information on compound absorption, distribution, metabolism and toxicity in addition to valuable efficacy data. I t is significantly lower throughput compared to cell-based assays. Disadvantage- poor relevance of some animal models to disease. Animal-based phenotypic screens 24

Animal-based phenotypic screens… :

Animal-based phenotypic screens… Less effect No effect effective ..... LEAD COMPOUND 25

Cell-based phenotypic assays :

Cell-based phenotypic assays Advances in new phenotypic screening technologies. Cell-based phenotypic assays usually use stem cells, immortalized cell lines (primary or engineered), or more recently, specific cell types of targeted organisms. Active compounds are identified that confer a change in a cellular phenotype such as killing cells, activating or inhibiting a signaling pathway, or normalizing a phenotypic change associated with cells. Types - Cell viability assays, cell signaling pathway assays, and disease related phenotypic assays . 26

Cell-based phenotypic assays :

Cell viability assays: M ost common phenotypic assays performed. The assay principle of cell viability assays involves mitochondrial activity, metabolism, activity of enzymes associated with viable or dead cells. Cell signaling pathway assays: Known signaling pathway such as a GPCR, nuclear receptor, transcriptional or ubiquitin–proteasome pathway is targeted. Targeting all proteins is the main advantage of a signaling pathway assay. Active compounds identified from signaling pathway-based screens may interact with molecular targets at any point or multiple points. Cell-based phenotypic assays 27

Cell-based phenotypic assays :

Disease related phenotypic assays : Many diseases are characterized by cellular phenotypic changes relative to healthy cells, such as morphological changes, or differences in protein translocation, expression, activity, or function . Measurements in DNA content, nuclear morphology and protein levels involved in the cell cycle can be used for screening of cell cycle modulators, such as mitotic inhibitors. Cell-based phenotypic assays 28

Cell-based phenotypic assays :

29 Cell-based phenotypic assays

Case study:

Case study 30

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Primary Screening and Microbiology The nematode, Nematospiroides dubius , was selected for the assay. Nematodes Infected mice were fed Milled Purina Lab Chow mixed with the fermentation product to be tested. After 14 days post infection, fecal pellets were examined for the presence of eggs. If eggs were absent , the mice were sacrificed and their small intestines examined for the presence of worms . This assay was relatively successful. Among the many thousands of cultures tested in this assay, about 1% were active in the first test. The culture, was named Streptomyces avermitilis . 31

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Chemistry Isolation: The avermectin complex, consisting of four major components designated A1a, A2a, B1a ,B2a and four lower homologs designated A1a, A2b, B1a,B2b was extracted with acetone from the mycelia of Streptomyces avermitilis. Separation of the A components from the Β components was achieved by partition chromatography with hexane- methylene chloride-methanol (10:10:1) over Sephadex LH-20. Structure Determination : On the basis of X-ray analysis the mass spectral fragmentation patterns, structure of avermectin was determined. 32

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Parasitological Evaluation : Two types of bioassay In one, compounds were tested in small laboratory animals infected with nematodes other than N. dubius . For example, test materials were given to jirds ( Meriones unguiculatus ) infected with Trichostrongylus colubriformis , and the animals were subsequently killed for determination of worm burden. 2. In the other, compounds were tested against a variety of nematodes in sheep. Compounds were similarly tested against several host including insects, mites, trematodes . This is in accord with reports that the avermectins disrupt GABA-mediated nerve transmission in nematodes and arthropods . 34


Conclusion Nematodes are one of the most notorious and stubborn problem for plants, animals, humans. There is a genuine need of new anthelmintic drugs and chemical molecules. Phenotypic screening is the traditional way of discovering drugs. Most of the First in class drugs were discovered using phenotypic screens. Streamlined protocols need to be adopted in case of plant parasitic nematodes on similar lines to discover new nematicides. 35

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Thank you 36

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