Drugs from the Sea: Conopeptides as Potential Therapeutics

Abstract

Marine cone snails from the genus Conus are estimated to consist of up to 700 species. These predatory molluscs have devised an efficient venom apparatus that allows them to successfully capture polychaete worms, other molluscs or in some cases fish as their primary food sources. The toxic venom used by the cone shells contains up to 50 different peptides that selectively inhibit the function of ion channels involved in the transmission of nerve signals in animals. Each of the 700 Conus species contains a unique set of peptides in their venom. Across the genus Conus, the conotoxins represent an extensive array of ion channel blockers each showing a high degree of selectivity for particular types of channels. We have undertaken a study of the conotoxins from Australian species of Conus that have the capacity to inhibit specifically the nicotinic acetylcholine receptors in higher animals. These conotoxins have been identified by mass spectroscopy and their peptide sequences in some cases deduced by the application of modern molecular biology to the RNA extracted from venom ducts. The molecular biological approach has proven more powerful than earlier protein/peptide based technique tor the detection of novel conotoxins [1,2]. Novel conotoxins detected in this way have been further screened for their abilities to modify the responses of tissues to pain stimuli as a first step in describing their potential as lead compounds for novel drugs. This review describes the progress made by several research groups to characterise the properties of conopeptides and to use them as drug leads for the development of novel therapeutics for the treatment of a range of neurological conditions.

Engineering stable peptide toxins by means of backbone cyclization: Stabilization of the α-conotoxin MII

“…These 12-to 30-aa peptides target membrane receptors with exquisite selectivity and potency and have become invaluable neurophysiological probes and drug leads. Recently, the CTX ziconotide (MVIIA) was approved for use in the treatment of severe chronic pain by the FDA, and other CTXs have entered clinical trials as treatments for pain (3,4). In addition, CTXs have played a critical role in dissecting the molecular mechanisms of ion channel and transporter functions in the nervous system (2).…”

Perspectivas da aplicação das conotoxinas bloqueadoras de canais para cálcio dependentes de voltagem no trauma medular

“…Para sua obtenção, ela é extraída dos ductos de veneno desses animais e purifi cada por fracionamento, pela técnica de cromatografi a líquida de alta efi ciência em fase reversa, baseada em superfície de óxidos inorgânicos (AGUILAR et al, 2009). A toxina purifi cada é composta por pequenos peptídeos, denominados conopeptídeos, variando o tamanho de oito a 31 aminoácidos, enriquecida com pontos de dissulfeto (SHEN et al, 2000), os quais mostraram resultados promissores em estudos experimentais de desordens neurológicas, como epilepsia (MALMBERG et al, 2003), Parkinson, Alzheimer, isquemia medular (LAVOR, 2013) e já são utilizados em síndromes neuropáticas de dores crônicas (LIVETT et al, 2004;MEHDIRATTA & SABERWAL, 2007).…”

“…As ômega-conotoxinas (ω-conotoxinas) são específi cas para CCDV, inibindo a liberação de neurotransmissores. Outras famílias bloqueiam receptores nicotínicos (alfa-e psi-conotoxina), canais para potássio voltagem dependentes (mu-e delta-conotoxina), receptores de serotonina (sigma-conotoxina) e inibição de canais iônicos inespecifi camente (gama-conotoxina) (LIVETT et al, 2004;MEHDIRATTA & SABERWAL, 2007;OLIVERA & TEICHERT, 2007).…”

One slip, and you're dead...

“…The toxin has since been developed as a drug called ziconotide and is now in advanced clinical trials for patients with cancer and AIDS who are suffering from pain that cannot be relieved by opiates 5 . Different groups of conotoxins -most known by various letters of the Greek alphabet -target other ion channels, such as those for sodium and potassium, or receptors and transporters for neurotransmitters such as glutamate, serotonin, neurotensin and noradrenaline 6,7 . "This is a real pharmaceutical cornucopia waiting to be tapped," says Bruce Livett of the University of Melbourne in Australia, who hopes soon to put an Ȋ-conotoxin, known as Vc1.1, into clinical trials for patients with diabetes who are suffering from the neuropathic pain that is a complication of the disease.…”