JD - Anthelmintics III Flashcards
What is the structure of ivermectin? (4)
- Macrocyclic lactone
- Disaccharide-oxy
- Spiroketal
- Benzofuran
What is the origin of ivermectin?
- Semi-synthetic derivative of a natural product from Streptomyces avermitilis
What are the uses of ivermectin? (2)
- Antiparasitic medication
- Treats parasitic infections (e.g., roundworms, mites, lice)
What is notable about ivermectin potency? (4)
Highly potent antiparasitic effective against a range of parasites, including:
-
Nematodes, such as:
- Dirofilaria immitis (heartworm) at 1 µg/kg
- Onchocerca volvulus (river blindness) at 200 µg/kg
- Other nematodes (e.g., roundworms, hookworms, lice)
*Not effective against trematodes (flukes) or cestodes (tapeworms) - Superior to diethylcarbamazine, which requires higher doses (10 mg/kg)
What are the effects of ivermectin on nematodes? (3)
- Paralysis
- Inhibits feeding
- Inhibits egg-laying
What is the mechanism of action of ivermectin? (2)
- Activates chloride channels in invertebrate muscle
- Causes paralysis with minimal effects on mammalian hosts
How was the ivermectin receptor identified in C. elegans? (4)
Cully et al. (1994) used expression cloning:
- Expressed C. elegans cDNA in Xenopus laevis oocytes
- Screened for ivermectin-induced currents via two-electrode voltage-clamp
- Results: Identified two receptor subunits (α and β)
α subunit: Confers glutamate sensitivity
β subunit: Modulates response to ivermectin
What is the structure of the ivermectin receptor? (3)
- A heteromeric protein complex forming a chloride ion channel
- Composed of five subunits arranged in a pentameric ring
- The α and β subunits are essential for ivermectin sensitivity.
How is C. elegans transgenics created? (3)
1) Clone ‘reporter construct’:
- Fuse a regulatory sequence (e.g., promoter) with a reporter gene (e.g., GFP or luciferase).
2) Inject adult worm:
- Inject the reporter construct into the gonad of an adult C. elegans.
- DNA integrates into the genome, and offspring inherit the transgene.
3) Phenotype progeny:
- Screen progeny for expression of the reporter gene to study regulatory sequence activity.
What is the effect of ivermectin on the pharynx of C. elegans? (2)
- Inhibits feeding by acting on a glutamate-gated chloride channel
- Model system for studying ivermectin’s mode of action
Why is ivermectin selectively toxic?
- Targets invertebrates due to glutamate-gated chloride channels absent in mammals
What are new-generation anthelmintics? (2)
Emodepsid:
- Macrocyclic lactone anthelmintic
- Effective against gastrointestinal nematodes
- Causes paralysis by acting on a calcium-activated K⁺ channel (slo-1)
AADs (Amino-acetonitrile derivatives):
- Break drug resistance in nematodes
- Potently inhibit motility
- Target nicotinic acetylcholine receptors (nAChRs) specific to nematodes
What are the effects of Emodepsid on C. elegans? (4)
- Slows development: Delays the developmental process.
- Inhibits locomotion: Impairs movement ability.
- Inhibits feeding: Reduces feeding behavior.
- Inhibits egg-laying: Suppresses egg production.
What causes emodepside resistance in C. elegans? (4)
- Resistance is linked to a mutation in an ion channel.
- Mapped to chromosome V, with candidate genes including slo-1.
- slo-1 null mutants show high resistance to emodepside.
- The emodepside receptor is likely a calcium-activated K⁺ channel.
What is the putative AAD receptor, and why is it selectively toxic?
- The AAD receptor is specific to nematodes, enabling selective targeting.
- This specificity makes AADs effective anthelmintic drugs with minimal impact on non-target organisms.
