Conotoxins: Therapeutic Potential and Application

Abstract

Abstract:The pharmacological variety of conotoxins, diverse peptides found in the venoms of marine cone snails, is well recognized. Venoms from each of the estimated 500 species of cone snails contain 50 to 200 distinct biologically active peptides. Most conotoxins characterized to date target receptors and ion channels of excitable tissues, such as ligandgated nicotinic acetylcholine, N-methyl-D-aspartate, and type 3 serotonin receptors, as well as voltage-gated calcium, sodium, and potassium channels, and G-protein-coupled receptors including α-adrenergic, neurotensin, and vasopressin receptors, and the norepinephrine transporter. Several conotoxins have shown promise in preclinical models of pain, convulsive disorders, stroke, neuromuscular block, and cardioprotection. The pharmacological selectivity of the conotoxins, coupled with the safety and efficacy demonstrated in preclinical models, has led to their investigation as human therapeutic agents. In the following review, we will survey the pharmacology and therapeutic rationale of those conotoxins with potential clinical application, and discuss the unique challenges that each will face in the course of their transition from venom component to human therapeutic.

Research on acute toxicity and analgesic activity of a fusion protein of omega-conotoxin mviia and thioredoxin

“…Conotoxin có thành phần là hỗn hợp các ñộc tố protein/peptide, enzyme hoặc các phân tử có khối lượng thấp. Đa số các loại conotoxin ñã ñược nghiên cứu thường có ñích tác dụng là các thụ thể trên màng tế bào hay là các kênh ion liên quan ñến mô cơ hoặc mô thần kinh [7]. Tùy theo cấu trúc và dược tính của các loại conotoxin khác nhau mà người ta xắp xếp chúng vào các siêu họ như A, M, O, P, S, T, I… [14].…”

“…Omega-conotoxin MVIIA có nhiều dược tính quý, có khả năng chữa các bệnh ñau mãn tính, ñau sau khi mổ, ñau do thần kinh bị tổn thương, ñột quỵ, nhồi máu cơ tim... [7,14]. Omega-conotoxin MVIIA là conotoxin ñầu tiên ñược phép sử dụng làm thuốc giảm ñau ở Mỹ và châu Âu với cái tên Prialt ® hay Ziconotid ® .…”

Using Drosophila behavioral assays to characterize terebrid venom-peptide bioactivity

“…Cone snail venom peptides molecularly target ion channels and receptors, and in the case of cone snails, have shown remarkable selectivity for certain channels and receptors [14][15][16] . Additionally, the compact size of conoidean venom peptides and their enhanced disulfidebridged stability make them good candidates for pharmaceutical drug discovery and development 17,18 . There are over 15,000 species of conoideans, with an estimated venom-peptide reservoir of over a million compounds 19 .…”

“…However, it is important to note that while evolutionary similar, teretoxin and conotoxin differ in size, structural integrity and complexity, suggesting that they might be applicable to different molecular applications 29 . The potential of novel attributes of teretoxins for combating human disease and disorder demands efficient strategies to characterize these promising bioactive peptides 17,31 .…”

Strategies for the Development of Conotoxins as New Therapeutic Leads

“…Conotoxins, isolated from the venom ducts of cone snails, constitute a large family of small, disulfide-rich peptides that have evolved to target a range of ion channels and receptors throughout the nervous system, usually with high potency and selectivity [4,5,6,7]. As such, many of these conotoxins have been used to gain further information about their target at the pharmacological, physiological or structural level [8,9,10,11]. They are relatively small peptides, typically eight to thirty amino acid residues in length that have been divided into different structural and pharmacological classes.…”