Cyclooctadepsipeptides–an anthelmintically active class of compounds exhibiting a novel mode of action.
Abstract: There are three major classes of anthelmintics for veterinary use: the benzimidazoles/prebenzimidazoles, the tetrahydropyrimidines/imidazothiazoles, and the macrocyclic lactones. In nematodes, there are five targets for the existing anthelmintics: the nicotinergic acetylcholine receptor which is the target of tetrahydropyrimidines/imidazothiazoles and indirectly that of the acetylcholineesterase inhibitors; the GABA receptor which is the target of piperazine, the glutamate-gated chloride channel as the target of the macrocyclic lactones, and beta-tubulin as the target of prebenzimidazoles/benzimidazoles. All these anthelmintics are now in serious danger because of the worldwide spread of resistant nematodes in sheep, cattle, horses and pigs. The class of cyclooctadepsipeptides has entered the scene of anthelmintic research in the early 1990s. PF1022A, the first anthelmintically active member, is a natural compound from the fungus Mycelia sterilia that belongs to the microflora of the leaves of the Camellia japonica. PF1022A contains 4 N-Methyl-L-leucines, 2 D-lactic acids and 2-D-phenyllactic acids arranged as a cyclic octadepsipeptide with an alternating L-D-L-configuration. Emodepside is a semisynthetic derivative of PF1022A with a morpholine ring at each of the two D-phenyllactic acids in para position. The anthelmintic activity is directed against gastrointestinal nematodes in chicken, mice, rats, meriones, dogs, cats, sheep, cattle and horses. Moreover, emodepside is active against Trichinella spiralis larvae in muscles, microfilariae and preadult filariae and Dictyocaulus viviparus. PF1022A and emodepside are fully effective against benzimidazole-, levamisole or ivermectin-resistant nematodes in sheep and cattle. In Ascaris suum both cyclooctadepsipeptides lead to paralysis indicating a neuropharmacological action of these compounds. Using a PF1022A-ligand immunoscreening of a cDNA library from Haemonchus contortus a cDNA clone of 3569 base pairs could be identified. This clone codes for a novel 110 kDa heptahelical transmembrane receptor, named HC110R. Database- and phylogenetic analysis reveals that this receptor is a homolog to B0457.1 from Caenorhabditis elegans and has significant similarity to latrophilins from human, cattle and rat. HC110R is located in the plasma membrane and in lysosomes and endosomes. Alpha-latrotoxin, the poison of the black widow spider, binds at a 54 kDa aminoterminal fragment of HC110R. After binding a Ca2+-influx into HEK293 cells is induced which can be blocked by EGTA, Cd2+ or nifedipin. PF1022A or emodepside also bind to this 54 kDa aminoterminal region of HC110R and interact with the functional responses of alpha-latrotoxin. In C. elegans antibodies against the C-or N-terminus of HC110R bind to the B0457.1 protein located in the pharynx. Electrophysiological studies reveal that emodepside inhibits pharyngeal pumping of the nematodes in a concentration dependent way with an IC(50) value of about 4 nM. Thus, it is tempting to speculate that emodepside exerts its action on nematodes via a latrophilin-like receptor which might have an important regulatory function on pharyngeal pumping.
Publication Date: 2003-09-19 PubMed ID: 13678839DOI: 10.1016/s0924-8579(03)00219-xGoogle Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Review
- Anthelmintic Resistance
- Anthelmintic Treatment
- Biochemistry
- Disease Management
- Disease Treatment
- Drug
- Equine Diseases
- Equine Health
- Genetics
- In Vitro Research
- In Vivo
- Laboratory Methods
- Molecular biology
- Nematodes
- Pharmacodynamics
- Pharmacokinetics
- Pharmacology
- Veterinary Medicine
- Veterinary Research
- Veterinary Science
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research paper explores how a group of compounds, called cyclooctadepsipeptides, can be used as alternative anthelmintics (worm medicines) for animals, due to their different mode of action which overcomes the issue of resistance in many gut worms to traditional drugs.
Introduction and Background
- The study focuses on cyclooctadepsipeptides, a class of compounds that have shown anthelmintic (worm-killing) activity, and propose a novel mode of action against parasites.
- The research comes as the effectiveness of the three main anthelmintics in use (benzimidazoles/prebenzimidazoles, tetrahydropyrimidines/imidazothiazoles, and macrocyclic lactones) is threatened by the global spread of resistance in nematodes infecting various farm animals and pets.
Research on Cyclooctadepsipeptides
- Cyclooctadepsipeptides became a focus of anthelmintic research in the early 90s, with PF1022A, a natural compound derived from the fungus Mycelia sterilia, found on Camellia japonica leaves, being the first to demonstrate such activity.
- Emodepside, a semi-synthetic derivative of PF1022A, showed effectiveness against several types of gastrointestinal nematodes found in a range of animals, from poultry to horses, and also against certain forms of filarial worms and lungworms.
- Both PF1022A and emodepside were found effective against nematodes resistant to the main classes of anthelmintics.
Mode of Action
- In a test with Ascaris suum (a species of parasitic roundworm), both types of cyclooctadepsipeptides caused paralysis, suggesting a neuropharmacological effect.
- A cDNA (complementary DNA) clone, coding for a novel 110 kDa heptahelical transmembrane receptor (named HC110R), was identified from a PF1022A-ligand immunoscreen of a cDNA library from Haemonchus contortus (a species of parasitic worm).
- HC110R was found to be similar to latrophilins (receptors that bind alpha-latrotoxin, the poison from the Black widow spider) and had significant similarity to those found in humans, cattle, and rats.
- Emodepside and PF1022A were found to bind to the same receptor fragment that alpha-latrotoxin binds to, interacting with its functional responses.
- In the nematode Caenorhabditis elegans, antibodies against the C-or N-terminus of HC110R was shown to bind to the B0457.1 protein located in the pharynx.
- Emodepside inhibited the pharyngeal pumping of the nematodes in a concentration-dependent manner, reinforcing the theory that it acts via a latrophilin-like receptor, which may regulate this activity in nematodes.
Cite This Article
APA
Harder A, Schmitt-Wrede HP, Krücken J, Marinovski P, Wunderlich F, Willson J, Amliwala K, Holden-Dye L, Walker R.
(2003).
Cyclooctadepsipeptides–an anthelmintically active class of compounds exhibiting a novel mode of action.
Int J Antimicrob Agents, 22(3), 318-331.
https://doi.org/10.1016/s0924-8579(03)00219-x Publication
Researcher Affiliations
- Bayer AG, BHC, AH-RD-Para, Alfred-Nobel-Strasse 50, D-40789 Manheim, Germany. achim-harder-ah@bayer.ag.de
MeSH Terms
- Animals
- Anthelmintics / chemistry
- Anthelmintics / classification
- Anthelmintics / pharmacology
- Binding Sites
- Depsipeptides
- Drug Resistance
- Helminth Proteins / genetics
- Helminth Proteins / metabolism
- Helminthiasis / drug therapy
- Helminthiasis, Animal / drug therapy
- Helminths / drug effects
- Humans
- Nematoda / drug effects
- Peptides, Cyclic / chemistry
- Peptides, Cyclic / pharmacology
- Phylogeny
Citations
This article has been cited 33 times.- Assmus F, Hoglund RM, Monnot F, Specht S, Scandale I, Tarning J. Drug development for the treatment of onchocerciasis: Population pharmacokinetic and adverse events modeling of emodepside.. PLoS Negl Trop Dis 2022 Mar;16(3):e0010219.
- Klöppel S, Richarz R, Wirtz DA, Vasenda N, König GM, Crüsemann M. A Specialized Dehydrogenase Provides l-Phenyllactate for FR900359 Biosynthesis.. Chembiochem 2022 May 18;23(10):e202100569.
- Krücken J, Holden-Dye L, Keiser J, Prichard RK, Townson S, Makepeace BL, Hübner MP, Hahnel SR, Scandale I, Harder A, Kulke D. Development of emodepside as a possible adulticidal treatment for human onchocerciasis-The fruit of a successful industrial-academic collaboration.. PLoS Pathog 2021 Jul;17(7):e1009682.
- Gillon JY, Dennison J, van den Berg F, Delhomme S, Dequatre Cheeseman K, Peña Rossi C, Strub Wourgaft N, Specht S, Pedrique B, Monnot F, Skrabs S, Rodriguez ML, Stass H. Safety, tolerability and pharmacokinetics of emodepside, a potential novel treatment for onchocerciasis (river blindness), in healthy male subjects.. Br J Clin Pharmacol 2021 Oct;87(10):3949-3960.
- Ramachandran G, Rajivgandhi GN, Murugan S, Alharbi NS, Kadaikunnan S, Khaled JM, Almanaa TN, Manoharan N, Li WJ. Anti-carbapenamase activity of Camellia japonica essential oil against isolated carbapenem resistant klebsiella pneumoniae (MN396685).. Saudi J Biol Sci 2020 Sep;27(9):2269-2279.
- Jimenez Castro PD, Mansour A, Charles S, Hostetler J, Settje T, Kulke D, Kaplan RM. Efficacy evaluation of anthelmintic products against an infection with the canine hookworm (Ancylostoma caninum) isolate Worthy 4.1F3P in dogs.. Int J Parasitol Drugs Drug Resist 2020 Aug;13:22-27.
- Gaens D, Leithäuser C, Hamann M, Geyer J. Adverse Drug Reactions After Administration of Emodepside/Praziquantel (Profender®) in an MDR1-Mutant Australian Shepherd Dog: Case Report.. Front Vet Sci 2019;6:296.
- Karpstein T, Pasche V, Häberli C, Scandale I, Neodo A, Keiser J. Evaluation of emodepside in laboratory models of human intestinal nematode and schistosome infections.. Parasit Vectors 2019 May 14;12(1):226.
- D'Amato A, Della Sala G, Izzo I, Costabile C, Masuda Y, De Riccardis F. Cyclic Octamer Peptoids: Simplified Isosters of Bioactive Fungal Cyclodepsipeptides.. Molecules 2018 Jul 19;23(7).
- McVeigh P, McCammick E, McCusker P, Wells D, Hodgkinson J, Paterson S, Mousley A, Marks NJ, Maule AG. Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes.. Int J Parasitol Drugs Drug Resist 2018 Apr;8(1):87-103.
- Abongwa M, Martin RJ, Robertson AP. A BRIEF REVIEW ON THE MODE OF ACTION OF ANTINEMATODAL DRUGS.. Acta Vet (Beogr) 2017 Jun;67(2):137-152.
- Kuesel AC. Research for new drugs for elimination of onchocerciasis in Africa.. Int J Parasitol Drugs Drug Resist 2016 Dec;6(3):272-286.
- Greenberg RM. Ion channels and drug transporters as targets for anthelmintics.. Curr Clin Microbiol Rep 2014 Dec;1(3-4):51-60.
- Panic G, Duthaler U, Speich B, Keiser J. Repurposing drugs for the treatment and control of helminth infections.. Int J Parasitol Drugs Drug Resist 2014 Dec;4(3):185-200.
- Sivanathan S, Scherkenbeck J. Cyclodepsipeptides: a rich source of biologically active compounds for drug research.. Molecules 2014 Aug 15;19(8):12368-420.
- McVeigh P, Atkinson L, Marks NJ, Mousley A, Dalzell JJ, Sluder A, Hammerland L, Maule AG. Parasite neuropeptide biology: Seeding rational drug target selection?. Int J Parasitol Drugs Drug Resist 2012 Dec;2:76-91.
- Wolstenholme AJ. Ion channels and receptor as targets for the control of parasitic nematodes.. Int J Parasitol Drugs Drug Resist 2011 Dec;1(1):2-13.
- Treger RS, Otchere J, Keil MF, Quagraine JE, Rai G, Mott BT, Humphries DL, Wilson M, Cappello M, Vermeire JJ. In vitro screening of compounds against laboratory and field isolates of human hookworm reveals quantitative differences in anthelmintic susceptibility.. Am J Trop Med Hyg 2014 Jan;90(1):71-4.
- Schwarz EM, Korhonen PK, Campbell BE, Young ND, Jex AR, Jabbar A, Hall RS, Mondal A, Howe AC, Pell J, Hofmann A, Boag PR, Zhu XQ, Gregory T, Loukas A, Williams BA, Antoshechkin I, Brown C, Sternberg PW, Gasser RB. The genome and developmental transcriptome of the strongylid nematode Haemonchus contortus.. Genome Biol 2013 Aug 28;14(8):R89.
- Roeber F, Jex AR, Gasser RB. Next-generation molecular-diagnostic tools for gastrointestinal nematodes of livestock, with an emphasis on small ruminants: a turning point?. Adv Parasitol 2013;83:267-333.
- Kulke D, Krücken J, Demeler J, Harder A, Mehlhorn H, von Samson-Himmelstjerna G. In vitro efficacy of cyclooctadepsipepdtides and aminophenylamidines alone and in combination against third-stage larvae and adult worms of Nippostrongylus brasiliensis and first-stage larvae of Trichinella spiralis.. Parasitol Res 2013 Jan;112(1):335-45.
- Accardi MV, Beech RN, Forrester SG. Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics.. Invert Neurosci 2012 Jun;12(1):3-12.
- Khanna V, Ranganathan S. In silico approach to screen compounds active against parasitic nematodes of major socio-economic importance.. BMC Bioinformatics 2011;12 Suppl 13(Suppl 13):S25.
- Komuniecki R, Law WJ, Jex A, Geldhof P, Gray J, Bamber B, Gasser RB. Monoaminergic signaling as a target for anthelmintic drug discovery: receptor conservation among the free-living and parasitic nematodes.. Mol Biochem Parasitol 2012 May;183(1):1-7.
- Jex AR, Liu S, Li B, Young ND, Hall RS, Li Y, Yang L, Zeng N, Xu X, Xiong Z, Chen F, Wu X, Zhang G, Fang X, Kang Y, Anderson GA, Harris TW, Campbell BE, Vlaminck J, Wang T, Cantacessi C, Schwarz EM, Ranganathan S, Geldhof P, Nejsum P, Sternberg PW, Yang H, Wang J, Wang J, Gasser RB. Ascaris suum draft genome.. Nature 2011 Oct 26;479(7374):529-33.
- Martin RJ, Buxton SK, Neveu C, Charvet CL, Robertson AP. Emodepside and SL0-1 potassium channels: a review.. Exp Parasitol 2012 Sep;132(1):40-6.
- Olliaro P, Seiler J, Kuesel A, Horton J, Clark JN, Don R, Keiser J. Potential drug development candidates for human soil-transmitted helminthiases.. PLoS Negl Trop Dis 2011 Jun;5(6):e1138.
- Silva JP, Ushkaryov YA. The latrophilins, "split-personality" receptors.. Adv Exp Med Biol 2010;706:59-75.
- Crisford A, Murray C, O'Connor V, Edwards RJ, Kruger N, Welz C, von Samson-Himmelstjerna G, Harder A, Walker RJ, Holden-Dye L. Selective toxicity of the anthelmintic emodepside revealed by heterologous expression of human KCNMA1 in Caenorhabditis elegans.. Mol Pharmacol 2011 Jun;79(6):1031-43.
- Traversa D, von Samson-Himmelstjerna G, Demeler J, Milillo P, Schürmann S, Barnes H, Otranto D, Perrucci S, di Regalbono AF, Beraldo P, Boeckh A, Cobb R. Anthelmintic resistance in cyathostomin populations from horse yards in Italy, United Kingdom and Germany.. Parasit Vectors 2009 Sep 25;2 Suppl 2(Suppl 2):S2.
- Gottstein B, Pozio E, Nöckler K. Epidemiology, diagnosis, treatment, and control of trichinellosis.. Clin Microbiol Rev 2009 Jan;22(1):127-45, Table of Contents.
- Verma S, Robertson AP, Martin RJ. Effects of SDPNFLRF-amide (PF1) on voltage-activated currents in Ascaris suum muscle.. Int J Parasitol 2009 Feb;39(3):315-26.
- Holden-Dye L, O'Connor V, Hopper NA, Walker RJ, Harder A, Bull K, Guest M. SLO, SLO, quick, quick, slow: calcium-activated potassium channels as regulators of Caenorhabditis elegans behaviour and targets for anthelmintics.. Invert Neurosci 2007 Dec;7(4):199-208.
Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
