CHAPTER 11. Engineering Venom Peptides to Improve Their Stability and Bioavailability

Akcan, Muharrem; Craik, David J.

doi:10.1039/9781849737876-00275

Cited by 4 publications

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References 42 publications

(46 reference statements)

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“…Over the last decade, cyclic peptides have been discovered in animals, plants, fungi, and bacteria and offer clues toward improving the stability of peptides (25)(26)(27). Head-to-tail cyclic peptides are typically more resistant to thermal or enzymatic degradation than their linear counterparts (28,29). Improving the stability of conotoxins in biological fluids using backbone cyclization was initially inspired by research into naturally occurring cyclic The authors declare that they have no conflicts of interest with the contents of this article.…”

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Backbone cyclization of analgesic conotoxin gexiva facilitates direct folding of the ribbon isomer

Huang

Kaas

et al. 2019

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Conotoxin GeXIVA inhibits the α9α10 nicotinic acetylcholine receptor (nAChR) and is analgesic in animal models of pain. α-Conotoxins have four cysteines that can have three possible disulfide connectivities: globular (Cys I-Cys III and Cys II-Cys IV), ribbon (Cys I-Cys IV and Cys II-Cys III), or bead (Cys I-Cys II and Cys III-Cys IV). Native α-conotoxins preferably adopt the globular connectivity, and previous studies of αconotoxins have focused on the globular isomers as the ribbon and bead isomers typically have lower potency at nAChRs than the globular form. A recent report showed that the bead and ribbon isomers of GeXIVA are more potent than the globular isomer, with low nanomolar half-maximal inhibitory concentrations (IC 50). Despite this high potency, the therapeutic potential of GeXIVA is limited, because like most peptides, it is susceptible to proteo-lytic degradation and is challenging to synthesize in high yield. Here we used backbone cyclization as a strategy to improve the folding yield as well as increase the serum stability of ribbon GeXIVA while preserving activity at the α9α10 nAChR. Specifically, cyclization of ribbon GeXIVA with a two-residue linker maintained the biological activity at the human α9α10 nAChR and improved stability in human serum. Short linkers led to selective formation of the ribbon disulfide isomer without requiring orthogonal protection. Overall, this study highlights the value of backbone cyclization in directing folding, improving yields, and stabilizing conotoxins with therapeutic potential.

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Backbone cyclization of analgesic conotoxin gexiva facilitates direct folding of the ribbon isomer

Huang

Kaas

et al. 2019

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“…peptides (29,30) and is a proven strategy to improve the stability of peptides, including conotoxins (31). For example, the stability of ␣-conotoxins MII, ImI, Vc1.1, RgIA, AuIB, and -conotoxin MrIA was significantly improved through backbone cyclization, and most of the cyclic peptides had similar or improved activity compared with their parent peptides (32).…”

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Backbone cyclization of analgesic conotoxin GeXIVA facilitates direct folding of the ribbon isomer

Huang

Kaas

et al. 2017

Journal of Biological Chemistry

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Conotoxin GeXIVA inhibits the α9α10 nicotinic acetylcholine receptor (nAChR) and is analgesic in animal models of pain. α-Conotoxins have four cysteines that can have three possible disulfide connectivities: globular (Cys-Cys and Cys-Cys), ribbon (Cys-Cys and Cys-Cys), or bead (Cys-Cys and Cys-Cys). Native α-conotoxins preferably adopt the globular connectivity, and previous studies of α-conotoxins have focused on the globular isomers as the ribbon and bead isomers typically have lower potency at nAChRs than the globular form. A recent report showed that the bead and ribbon isomers of GeXIVA are more potent than the globular isomer, with low nanomolar half-maximal inhibitory concentrations (IC). Despite this high potency, the therapeutic potential of GeXIVA is limited, because like most peptides, it is susceptible to proteolytic degradation and is challenging to synthesize in high yield. Here we used backbone cyclization as a strategy to improve the folding yield as well as increase the serum stability of ribbon GeXIVA while preserving activity at the α9α10 nAChR. Specifically, cyclization of ribbon GeXIVA with a two-residue linker maintained the biological activity at the human α9α10 nAChR and improved stability in human serum. Short linkers led to selective formation of the ribbon disulfide isomer without requiring orthogonal protection. Overall, this study highlights the value of backbone cyclization in directing folding, improving yields, and stabilizing conotoxins with therapeutic potential.

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Amide‐Forming Ligation Reactions

2019

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One of the long‐standing pursuits of synthetic organic chemists is the development of chemical methods for the synthesis of peptides and proteins as tools for understanding biological processes and providing therapeutic solutions to human diseases. The advent of chemoselective ligation reactions for the chemical synthesis of peptides and proteins has enabled synthetic chemists to realize this long‐held dream. In an amide‐forming ligation reaction, two uniquely placed functional groups within the peptide allow peptide or protein segments to be joined in a chemoselective manner with an amide bond. In this chapter, some of the early methods based on principles of the capture/rearrangement strategy for ligation of peptides are catalogued, followed by some of the most versatile and well‐established contemporary methods for the preparation of linear/cyclic peptides and proteins such as the native chemical ligation (NCL) and the α‐ketoacid–hydroxylamine (KAHA) ligation. The chapter concludes with some of the most promising new generation ligation methods such as the potassium acyltrifluoroborate–hydroxylamine (KAT) ligation. The tremendous progress in the past two decades in the development of several ligation methods that rely on a pair of unique functional groups is set to expand the horizons of fully functional proteins and multi‐protein assemblies that are purely synthetically prepared. Although contemporary ligation reactions do not match the speed and efficiency at which proteins are assembled in biological systems, the repertoire of chemoselective amide‐forming ligation methods has already enabled synthetic protein chemistry to surpass biology in terms of chemical and structural diversity.

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CHAPTER 11. Engineering Venom Peptides to Improve Their Stability and Bioavailability

Cited by 4 publications

References 42 publications

Backbone cyclization of analgesic conotoxin gexiva facilitates direct folding of the ribbon isomer

Backbone cyclization of analgesic conotoxin gexiva facilitates direct folding of the ribbon isomer

Backbone cyclization of analgesic conotoxin GeXIVA facilitates direct folding of the ribbon isomer

Amide‐Forming Ligation Reactions

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