Cyclisation of Disulfide‐Rich Conotoxins in Drug Design Applications

Wu, Xiaosa; Huang, Yen‐Hua; Kaas, Quentin; Craik, David J.

doi:10.1002/ejoc.201600402

Cited by 15 publications

(10 citation statements)

References 138 publications

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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). Most notably, Vc1.1 became orally active in animal models of pain after backbone cyclization (33).…”

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confidence: 99%

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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confidence: 99%

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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“…To test the significance of our approach, we analyzed the impact of one linker in a functional assay. Since the repetition of similar consecutive amino acids can lead to some difficulties [56], the top-ranked sequence AGG was discarded; instead, UII was cyclized with the sequence GAG, leading to the LV-4130 cyclic peptide. The head-to-tail cyclized peptide underwent synthesis and functional tests (see Methods).…”

Section: Application To Urotensin IImentioning

confidence: 99%

Head-to-tail peptide cyclization: new directions and application to urotensin II and Nrf2

Karami

Murail

Giribaldi

et al. 2022

Preprint

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Peptides have recently re-gained interest as therapeutic candidates but their development remains confronted with several limitations including low bioavailability. Backbone head-to-tail cyclization is one effective strategy of peptide-based drug design to stabilize the conformation of bioactive peptides while preserving peptide properties in terms of low toxicity, binding affinity, target selectivity and preventing enzymatic degradation. However, very little is known about the sequence-structure relationship requirements of designing linkers for peptide cyclization in a rational manner. Recently, we have shown that large scale data-mining of available protein structures can lead to the precise identification of protein loop conformations, even from remote structural classes. Here, we transpose this approach to head-to-tail peptide cyclization. Firstly we show that given a linker sequence and the conformation of the linear peptide, it is possible to accurately predict the cyclized peptide conformation improving by over 1 A over pre-existing protocols. Secondly, and more importantly, we show that is is possible to elaborate on the information inferred from protein structures to propose effective candidate linker sequences constrained by length and amino acid composition, providing the first framework for the rational peptide head-to-tail cyclization. As functional validation, we apply it to the design of a head-to-tail cyclized derivative of urotensin II, an 11-residue long peptide which exerts a broad array of biologic activities, making its cognate receptor a valuable and innovative therapeutic or diagnostic target. We propose a three amino acid candidate linker, leading to the first synthesized 14-residue long cyclic UII analogue with excellent retention of in vitro activity.

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“…69,70 Backbone cyclization is a common method in peptide engineering to prevent degradation by exoproteases, and this has been applied to a number of conotoxins. 23,33 Synthetic cyclization involves extending and connecting the N-and C-termini to form a loop, and generally leaving the rest of the peptide in its natural fold. This can be done by linkers of various lengths to preserve the natural structure of the bioactive peptide.…”

Section: Rsc Medicinal Chemistry Reviewmentioning

confidence: 99%