Abstract
The peptides present in the venoms of marine snails are used by the snails to capture prey, but they have also attracted the interest of drug designers because of their potent activity against therapeutically important targets. These peptides are typically disulfiderich and target a wide range of ion channels, transporters and receptors with exquisite selectivity. In this article, we discuss structural and biological studies on several classes of conotoxins that have potential as drug leads for the treatment of pain. The chemical re-engineering of conotoxins via cyclization has been particularly valuable in improving their biopharmaceutical properties. An excellent example is the α-conotoxin Vc1.1, for which several cyclized analogs have been made. One of them was shown to be orally active in a rat pain model and this analog is currently undergoing pre-clinical development for the treatment of neuropathic pain. Several other α-conotoxins, including ImI, AuIB and MII, have proved amenable to cyclization and in all cases improvements in stability are obtained upon cyclization, suggesting that cyclization is a generally applicable approach to conotoxin stabilization. A variety of other chemical re-engineering approaches have also been used. Minor re-engineering of -conotoxin MrIa to convert its N-terminal residue to pyroglutamic acid proved particularly successful and the modified derivative, Xen2174, is currently in clinical trials for neuropathic pain.
Keywords: Conotoxin, cyclic peptides, cyclization, drug design, pain, venoms, conopeptides, neurodegenerative diseases, amide chemical shifts, oxytocin
Current Pharmaceutical Design
Title: Engineering of Conotoxins for the Treatment of Pain
Volume: 17 Issue: 38
Author(s): Bodil B. Carstens, Richard J. Clark, Norelle L. Daly, Peta J. Harvey, Quentin Kaas and David J. Craik
Affiliation:
Keywords: Conotoxin, cyclic peptides, cyclization, drug design, pain, venoms, conopeptides, neurodegenerative diseases, amide chemical shifts, oxytocin
Abstract: The peptides present in the venoms of marine snails are used by the snails to capture prey, but they have also attracted the interest of drug designers because of their potent activity against therapeutically important targets. These peptides are typically disulfiderich and target a wide range of ion channels, transporters and receptors with exquisite selectivity. In this article, we discuss structural and biological studies on several classes of conotoxins that have potential as drug leads for the treatment of pain. The chemical re-engineering of conotoxins via cyclization has been particularly valuable in improving their biopharmaceutical properties. An excellent example is the α-conotoxin Vc1.1, for which several cyclized analogs have been made. One of them was shown to be orally active in a rat pain model and this analog is currently undergoing pre-clinical development for the treatment of neuropathic pain. Several other α-conotoxins, including ImI, AuIB and MII, have proved amenable to cyclization and in all cases improvements in stability are obtained upon cyclization, suggesting that cyclization is a generally applicable approach to conotoxin stabilization. A variety of other chemical re-engineering approaches have also been used. Minor re-engineering of -conotoxin MrIa to convert its N-terminal residue to pyroglutamic acid proved particularly successful and the modified derivative, Xen2174, is currently in clinical trials for neuropathic pain.
Export Options
About this article
Cite this article as:
B. Carstens Bodil, J. Clark Richard, L. Daly Norelle, J. Harvey Peta, Kaas Quentin and J. Craik David, Engineering of Conotoxins for the Treatment of Pain, Current Pharmaceutical Design 2011; 17 (38) . https://dx.doi.org/10.2174/138161211798999401
DOI https://dx.doi.org/10.2174/138161211798999401 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Immunotherapy Strategies for Spinal Cord Injury
Current Pharmaceutical Biotechnology Animal Models for the Development of New Neuropharmacological Therapeutics in the Status Epilepticus
Current Neuropharmacology Pedunculopontine Nucleus Stimulation in Intractable Epilepsy: A Recent Patent on Deep Brain Stimulation Therapy
Recent Patents and Topics on Imaging (Discontinued) The Progress of Epilepsy after Stroke
Current Neuropharmacology Inhibition of Histone Deacetylases: A Pharmacological Approach to the Treatment of Non-Cancer Disorders
Current Topics in Medicinal Chemistry The Challenge of microRNA as a Biomarker of Epilepsy
Current Neuropharmacology The Pharmacogenetics of CYP2C9 and CYP2C19: Ethnic Variation and Clinical Significance
Current Clinical Pharmacology Organic Lesions in the Brain MRI of Children with Febrile Seizure
Current Medical Imaging A Role of GABA Analogues in the Treatment of Neurological Diseases
Current Medicinal Chemistry GABAergic Drugs for the Treatment of Migraine
CNS & Neurological Disorders - Drug Targets The Role of ABC and SLC Transporters in the Pharmacokinetics of Dietary and Herbal Phytochemicals and their Interactions with Xenobiotics
Current Drug Metabolism Ethanolamine: A Potential Promoiety with Additional Effects on the Brain
CNS & Neurological Disorders - Drug Targets Vagus Nerve Stimulation as a Treatment for Refractory Epilepsy: A 15-Year Experience in an Italian Tertiary – Care Epilepsy Center
Letters in Drug Design & Discovery Synthesis and Anticonvulsant Activity of N-(trans)- 3-phenylprop-2-en-1-yl (Cinnamyl) Derivatives of Aminoalkanols
Letters in Drug Design & Discovery Oxidative Stress in Traumatic Brain Injury
Current Medicinal Chemistry Commonalities in Biological Pathways, Genetics, and Cellular Mechanism between Alzheimer Disease and Other Neurodegenerative Diseases: An In Silico-Updated Overview
Current Alzheimer Research Cellular Functions of Vaults and their Involvement in Multidrug Resistance
Current Drug Targets Therapeutic Potential of Hepatocyte Growth Factor for Treating Neurological Diseases
Current Drug Therapy Targeting Cancer Stem Cells with Repurposed Drugs to Improve Current Therapies
Recent Patents on Anti-Cancer Drug Discovery Symptomatic Treatment of Chronic Neuropathic Pain with Gabapentin Clinical Practice and Research Prospective
Current Neuropharmacology