From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules

Abstract

Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted.

Oxidative Cyclization in Natural Product Biosynthesis

“…142 The compound is an acetylcholine agonist and has been used as skeletal muscle relaxant in African arrow poison. 143,144 The biosynthesis involves a heterodimeric radical coupling between the enantiomers ( R )- N -methyl-coclaurine ( 155 ) and ( S )- N -methyl-coclaurine ( 157 ) (Scheme 27). Both building blocks are derived from dopamine and 4-hydroxyphenylacetaldehyde via Pictet-Spengler reaction (Section 3.2.2).…”

A tale of ligands big and small: An update on how pentameric ligand-gated ion channels interact with agonists and proteins

“…In many cases, nature provides useful blueprints for such drug candidates in the form of peptide toxins that are already highly evolved to develop high affinity and specificity to their protein target. However, examples among pLGICs have remained scarce, with the exception of the reasonably well-characterised interactions of the orthosteric binding site of nAChRs with α-bungarotoxin and conotoxins [74]. A recent breakthrough came from the discovery of the first GABAR-specific toxins from coral snake venom [75], which potently modulate GABA A R activity.…”

Effects of Venoms on Largeconductance Cationic Channels on the Inner Nuclear Membrane of Rat Cerebellum Purkinje Neurons

“…Серед досліджених речовин отрути чоти рьох змій (N. kaouthia, B. fasciatus, V. renardi, B. arietans) містять токсини, які є ефективними блокаторами ацетилхолінових рецепторів нікотинового типу (nicotinic acetylcholine receptors, nAChRs) [9][10][11][12].Вони відносяться до рецепторів м'язового типу і їх блокування у ссавців компонентами отрут призводить до зупинки дихання та смерті. Найчастіше як блокатори AChRs використовуються нейротоксини кобри та крайта.…”