Structure-Activity Studies on Alpha-Conotoxins

Abstract

Conotoxins are small bioactive highly structured peptides from the venom of marine cone snails (genus Conus). Over the past 50 million years these molluscs have developed a complex venom cocktail for each species that is comprised of 100-2000 distinct cysteine- rich peptides for prey capture and defence. This review focuses on an important and well-studied class of conotoxins, the α- conotoxins. These α-conotoxins are potent and selective antagonists of various subtypes of the nicotinic acetylcholine receptors (nAChRs). Key structure-activity relationship studies are presented to illustrate the common motifs, structural features and pharmacophores that define this interesting peptide class. Additionally, their synthesis, chemical modifications, the development of more selective and stable analogues and their therapeutic potential are discussed.

Key Residues in the Nicotinic Acetylcholine Receptor β2 Subunit Contribute to α-Conotoxin LvIA Binding

“…5A). The F119Q mutation resulted in better complementarity at the interface by creating further interactions, especially with LvIA residues Val 10 and Pro 13 , resulting in the largest buried surface area among all mutants in this study, in agreement with the highest inhibitory activity of LvIA among all mutants.…”

“…␣-Conotoxins (␣-CTxs) are a rich source of highly selective ligands that discriminate among different nAChR subtypes (13)(14)(15). ␣-CTxs contain two conserved disulfide bridges and are classified into several structural subfamilies according to the number of residues in the two backbone loops bracketed by cysteine residues, the largest subfamilies being the 4/7, 4/6, 4/5, 4/4, 4/3, and 3/5 ␣-CTxs.…”

Key Structural Determinants in the Agonist Binding Loops of Human β2 and β4 Nicotinic Acetylcholine Receptor Subunits Contribute to α3β4 Subtype Selectivity of α-Conotoxins

“…␣4/3, ␣4/4, and ␣4/7) (8). Individual ␣-conotoxins have their own selectivity profile and can discriminate between different nAChR subunit combinations and stoichiometries (9,10).…”

Molecular Basis for Differential Sensitivity of α-Conotoxin RegIIA at Rat and Human Neuronal Nicotinic Acetylcholine Receptors

“…for different receptor subtypes (Terlau and Olivera, 2004;Muttenthaler et al, 2011;Lebbe et al, 2014). They are also promising lead compounds for drugs that target pathophysiological conditions related to nAChRs, such as chronic pain, cancers, and addiction (Olivera et al, 2008;Brady et al, 2013;Schroeder et al, 2013).…”

“…a-Conotoxins are classified as selective antagonists of muscle and neuronal nAChRs and are promising pharmacological probes and potential therapeutics (Olivera et al, 2008;Muttenthaler et al, 2011;Lebbe et al, 2014). a4/7-Conotoxin RegIIA, isolated from the venom of Conus regius, has previously been characterized as a potent inhibitor of rat a3b2, a3b4, and human a7 nAChRs at nanomolar concentrations (Franco et al, 2012).…”