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Facile Chemoselective Modification of Thioethers Generates Chiral Center-Induced Helical Peptides

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Peptide Conjugation

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2355))

Abstract

The modulation of protein-protein interactions (PPIs) is a promising way for interrogating disease. Stapled peptides that stabilize peptides into a fixed α-helical conformation via chemical means are important representative compounds for regulating PPIs. The effect of the secondary conformation of peptides on the biophysical properties has not been explicitly elucidated due to the difficulty of obtaining peptide epimers with the same chemical composition but different conformations. Herein, we systematically designed and demonstrated the concept of “Chiral Center-Induced Helicity” (CIH) to stabilize the secondary structure of peptides. By introducing a precise R-configuration chiral center on the side-ring of a peptide, researchers can decisively regulate the secondary structure of peptides. Through the study of CIH peptides, we found that increasing the helicity can significantly enhance the stability of peptides and improve the cell membrane penetrating capability of the peptides. Moreover, the substitution group in the chiral center could contribute to additional interactions with the binding groove, which shows great significance for fragment-based drug design. This chapter will focus on the method involved in this research, including specific protocols of the synthesis and basic characterization of CIH peptides in Subheading 3.1. In addition, we have also extended the concept of CIH to dual-chiral center systems, including sulfoxide-based and sulfonium-based in-tether chiral center peptides, which we will introduce in Subheadings 3.2 and 3.3.

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Acknowledgments

We acknowledge financial support from the Natural Science Foundation of China grants 21778009, 21977010, 81701818, and 51803006; the Natural Science Foundation of Guangdong Province, 2020A1515010522; the Shenzhen Science and Technology Innovation Committee, JCYJ20180507181527112 and JCYJ201805081522131455. 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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Authors and Affiliations

  1. State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China

    Yinghuan Liu, Kuan Hu, Feng Yin & Zigang Li

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  1. Yinghuan Liu
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  2. Kuan Hu
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  3. Feng Yin
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  4. Zigang Li
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Corresponding author

Correspondence to Zigang Li .

Editor information

Editors and Affiliations

  1. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, Australia

    Waleed M. Hussein

  2. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, Australia

    Rachel J. Stephenson

  3. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, Australia

    Istvan Toth

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Liu, Y., Hu, K., Yin, F., Li, Z. (2021). Facile Chemoselective Modification of Thioethers Generates Chiral Center-Induced Helical Peptides. In: Hussein, W.M., Stephenson, R.J., Toth, I. (eds) Peptide Conjugation. Methods in Molecular Biology, vol 2355. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1617-8_23

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  • DOI: https://doi.org/10.1007/978-1-0716-1617-8_23

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1616-1

  • Online ISBN: 978-1-0716-1617-8

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