title: An In-tether Chiral Center Modulates the Helicity, Cell Permeability, and Target Binding Affinity of a Peptide.
abstract: The addition of a precisely positioned chiral center in the tether of a constrained peptide is reported, yielding two separable peptide diastereomers with significantly different helicity, as supported by circular dichroism (CD) and NMR spectroscopy. Single crystal X-ray diffraction analysis suggests that the absolute configuration of the in-tether chiral center in helical form is R, which is in agreement with theoretical simulations. The relationship between the secondary structure of the short peptides and their biochemical/biophysical properties remains elusive, largely because of the lack of proper controls. The present strategy provides the only method for investigating the influence of solely conformational differences upon the biochemical/biophysical properties of peptides. The significant differences in permeability and target binding affinity between the peptide diastereomers demonstrate the importance of helical conformation.
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Kuan
authors.initials: K
authors.lastname: Hu
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Geng
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Qingzhou
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Qisong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Mingsheng
authors.initials: M
authors.lastname: Xie
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Chengjie
authors.initials: C
authors.lastname: Sun
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Huacan
authors.initials: H
authors.lastname: Lin
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Biology, Southern University of Science and Technology, Shenzhen, 518055, China. wangtao@sustc.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. wuyd@pkusz.edu.cn.
authors.forename: Yun-Dong
authors.initials: YD
authors.lastname: Wu
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. lizg@pkusz.edu.cn.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002463:Cell Membrane Permeability; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010539:Permeability; D017433:Protein Structure, Secondary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D047628:Estrogen Receptor alpha; D008024:Ligands; D010455:Peptides; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: cell permeability; chirality; helicity; stapled peptide; target binding affinity