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The Chemical Synthesis of α-Conotoxins and Structurally Modified Analogs with Enhanced Biological Stability

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Peptide Modifications to Increase Metabolic Stability and Activity

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1081))

Abstract

α-Conotoxins are peptide neurotoxins isolated from the venom ducts of carnivorous marine cone snails that exhibit exquisite pharmacological potency and selectivity for various nicotinic acetylcholine receptor subtypes. As such, they are important research tools and drug leads for treating various diseases of the central nervous system, including pain and tobacco addiction. Despite their therapeutic potential, the chemical synthesis of α-conotoxins for use in structure–activity relationship studies is complicated by the possibility of three disulfide bond isomers, where inefficient folding methods can lead to a poor recovery of the pharmacologically active isomer. In order to achieve higher yields of the native isomer, especially in high-throughput syntheses it is necessary to select appropriate oxidative folding conditions. Moreover, the poor biochemical stability exhibited by α-conotoxins limits their general therapeutic applicability in vivo. Numerous strategies to enhance their stability including the substitution of disulfide bond with diselenide bond and N-to-C cyclization via an oligopeptide spacer have successfully overcome these limitations. This chapter describes methods for performing both selective and nonselective disulfide bond oxidation strategies for controlling the yields and formation of α-conotoxin disulfide bond isomers, as well as methods for the production of highly stable diselenide-containing and N-to-C cyclized conotoxin analogs.

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Acknowledgment

The authors acknowledge financial support by the James and Esther King Biomedical Research Program (New Investigator Grant, 1KN02-33990), the Arthritis and Chronic Pain Research Institute, and the State of Florida.

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Authors and Affiliations

  1. Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA

    Jayati Banerjee, Reena Gyanda, Yi-Pin Chang & Christopher J. Armishaw

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  1. Jayati Banerjee
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  2. Reena Gyanda
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  3. Yi-Pin Chang
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  4. Christopher J. Armishaw
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Editors and Affiliations

  1. Torrey Pines Institute for Molecular Stu, Port St. Lucie, Florida, USA

    Predrag Cudic

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Banerjee, J., Gyanda, R., Chang, YP., Armishaw, C.J. (2013). The Chemical Synthesis of α-Conotoxins and Structurally Modified Analogs with Enhanced Biological Stability. In: Cudic, P. (eds) Peptide Modifications to Increase Metabolic Stability and Activity. Methods in Molecular Biology, vol 1081. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-652-8_2

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  • DOI: https://doi.org/10.1007/978-1-62703-652-8_2

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-651-1

  • Online ISBN: 978-1-62703-652-8

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