Search

Abstract: Cone snail venom is a rich source of bioactives, in particular small disulfide rich peptides that disrupt synaptic transmission. Here, we report the discovery of conomap-Vt (Conp-Vt), an unusual linear tetradecapeptide isolated from Conus vitulinus venom. The sequence displays no homology to known conopeptides, but displays significant homology to peptides of the MATP (myoactive tetradecapeptide) family, which are important endogenous neuromodulators in molluscs, annelids and insects. Conp-Vt showed potent excitatory activity in several snail isolated tissue preparations. Similar to ACh, repeated doses of Conp-Vt were tachyphylactic. Since nicotinic and muscarinic antagonists failed to block its effect and Conp-Vt desensitised tissue remained responsive to ACh, it appears that Conp-Vt contractions were non-cholinergic in origin. Finally, biochemical studies revealed that Conp-Vt is the first member of the MATP family with a d-amino acid. Interestingly, the isomerization of l-Phe to d-Phe enhanced biological activity, suggesting that this post-translational modified conopeptide may have evolved for prey capture. [Copyright &y& Elsevier]

Abstract: A number of ω-conotoxin GVIA mimetics based on an anthranilamide core were prepared and tested for their affinity for rat brain Cav2.2 channels. Features such as the presence of hydroxyl and fluoro substituents on the tyrosine side chain mimic, the length of the chains on the lysine/arginine side chain mimics and the use of diguanidino and diamino substituents rather than mono-guanidine/mono-amine substitution were examined. The diguanidinylated compounds proved to be the most active and deletion of the hydroxyl substituent had a limited influence on activity. The SAR associated with variation in the lysine/arginine side chain mimics was not strong. The introduction of a fluoro substituent into the tyrosine mimic produced the most active compound prepared in this study (2g), with an EC50 at rat brain Cav2.2 channels of 6μM. [Copyright &y& Elsevier]

Abstract: We report the synthesis and biological activity of a low molecular weight non-peptidic mimic of the analgesic peptide ω-conotoxin GVIA. The molecular weight of this compound presents a reduction by 193g/mol compared to a previously reported lead. This compound exhibits an EC50 of 5.8μM and is accessible in only six synthetic steps compared to the original lead (13 steps). We also report several improvements to the original synthetic route. [Copyright &y& Elsevier]