Twin disulfides for orthogonal disulfide pairing and the directed folding of multicyclic peptides

ABSTRACT Multicyclic peptides are emerging as an exciting platform for drug and targeted ligand discovery owing to their expected greater target affinity/selectivity/stability versus linear

or monocyclic peptides. However, although the precise pairing of cysteine residues in proteins is routinely achieved in nature, the rational pairing of cysteine residues within polypeptides

is a long-standing challenge for the preparation of multicyclic species containing several disulfide bridges. Here, we present an efficient and straightforward approach for directing the

intermolecular and intramolecular pairing of cysteine residues within peptides using a minimal CXC motif. Orthogonal disulfide pairing can be exploited in complex redox media to rationally

produce dimeric peptides and bi/tricyclic peptides from fully reduced peptides containing 1–6 cysteine residues. This strategy, which does not rely on extensive manipulation of the primary

sequence, post-translational modification or protecting groups, should greatly benefit the development of multicyclic peptide therapeutics and targeting ligands. Access through your

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BEING VIEWED BY OTHERS TRISCYSTEINE DISULFIDE-DIRECTING MOTIFS ENABLING DESIGN AND DISCOVERY OF MULTICYCLIC PEPTIDE BINDERS Article Open access 06 September 2024 NON-SYMMETRIC STAPLING OF

NATIVE PEPTIDES Article 04 April 2024 DE NOVO DESIGN AND DIRECTED FOLDING OF DISULFIDE-BRIDGED PEPTIDE HETERODIMERS Article Open access 22 March 2022 REFERENCES * Hamada, Y. & Shioiri,

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  Download references ACKNOWLEDGEMENTS C.W. acknowledges a postdoctoral fellowship from the ETHZ (FEL-09 10-1). AUTHOR INFORMATION Author notes * Chuanliu Wu Present address: Present

address: Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China, AUTHORS AND AFFILIATIONS * Department of Chemistry and Applied

Biosciences, Swiss Federal Institute of Technology Zürich (ETHZ), Institute of Pharmaceutical Sciences, Wolfgang-Pauli Strasse 10, HCl J 396.4, Zürich, 8093, Switzerland Chuanliu Wu, 

Jean-Christophe Leroux & Marc A. Gauthier Authors * Chuanliu Wu View author publications You can also search for this author inPubMed Google Scholar * Jean-Christophe Leroux View author

publications You can also search for this author inPubMed Google Scholar * Marc A. Gauthier View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS

C.W. designed, performed and analysed experiments. J-C.L. and M.A.G. designed and analysed experiments. All authors contributed to writing the manuscript. CORRESPONDING AUTHORS

Correspondence to Jean-Christophe Leroux or Marc A. Gauthier. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION

SUPPLEMENTARY INFORMATION Supplementary information (PDF 1890 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wu, C., Leroux, JC. & Gauthier, M.

Twin disulfides for orthogonal disulfide pairing and the directed folding of multicyclic peptides. _Nature Chem_ 4, 1044–1049 (2012). https://doi.org/10.1038/nchem.1487 Download citation *

Received: 02 May 2012 * Accepted: 25 September 2012 * Published: 28 October 2012 * Issue Date: December 2012 * DOI: https://doi.org/10.1038/nchem.1487 SHARE THIS ARTICLE Anyone you share the

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