Abstract
Over the past two decades, significant efforts have invested in the development of strategies for the stabilization of macrocyclic peptides with α-helix structure by stapling their architectures. These strategies can be divided into two categories: side chain to side chain cross-linking and N-terminal helix nucleation. These stable macrocyclic peptides have been applied in PPI inhibitors and self-assembly materials. Compared with unmodified short peptides, stable α-helix macrocyclic polypeptides have better biophysical properties including higher serum stability, cell permeability, and higher target affinity. This chapter will systematically introduce approaches for helical stabilization of peptide macrocycles, such as ring-closing metathesis (RCM), lactamisation, cycloadditions, reversible reactions, thioether formation as well as newly found sulfonium center formation and the common use of helical stabilized macrocyclic peptides.
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Acknowledgments
We acknowledge financial support from the Natural Science Foundation of China grants 21778009, and 21977010; National Key Research and Development Program “Synthetic Biology” Key Special Project of China, 2018YFA0902504; the Natural Science Foundation of Guangdong Province, 2020A1515010522; the Shenzhen Science and Technology Innovation Committee, JCYJ20180507181527112, JCYJ201805081522131455, and JCYJ20170817172023838. We acknowledge financial support from Beijing National Laboratory of Molecular Science open grant BNLMS20160112 and Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions grant 2019SHIBS0004. This work is supported by High-Performance Computing Platform of Peking University.
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Yang, F., Yin, F., Li, Z. (2022). Helical Stabilization of Peptide Macrocycles by Stapled Architectures. In: Coppock, M.B., Winton, A.J. (eds) Peptide Macrocycles. Methods in Molecular Biology, vol 2371. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1689-5_21
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DOI: https://doi.org/10.1007/978-1-0716-1689-5_21
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