title: Design of High-Affinity Stapled Peptides To Target the Repressor Activator Protein 1 (RAP1)/Telomeric Repeat-Binding Factor 2 (TRF2) Protein-Protein Interaction in the Shelterin Complex.
abstract: Shelterin, a six-protein complex, plays a fundamental role in protecting both the length and the stability of telomeres. Repressor activator protein 1 (RAP1) and telomeric repeat-binding factor 2 (TRF2) are two subunits in shelterin that interact with each other. Small-molecule inhibitors that block the RAP1/TRF2 protein-protein interaction can disrupt the structure of shelterin and may be employed as pharmacological tools to investigate the biology of shelterin. On the basis of the cocrystal structure of RAP1/TRF2 complex, we have developed first-in-class triazole-stapled peptides that block the protein-protein interaction between RAP1 and TRF2. Our most potent stapled peptide binds to RAP1 protein with a Ki value of 7 nM and is >100 times more potent than the corresponding wild-type TRF2 peptide. On the basis of our high-affinity peptides, we have developed and optimized a competitive, fluorescence polarization (FP) assay for accurate and rapid determination of the binding affinities of our designed compounds and this assay may also assist in the discovery of non-peptide, small-molecule inhibitors capable of blocking the RAP1/TRF2 protein-protein interaction.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Department of Pharmacology, ∥Comprehensive Cancer Center, ⊥Department of Biological Chemistry, and #Howard Hughes Medical Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Xu
authors.initials: X
authors.lastname: Ran
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Department of Pharmacology, ∥Comprehensive Cancer Center, ⊥Department of Biological Chemistry, and #Howard Hughes Medical Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Department of Pharmacology, ∥Comprehensive Cancer Center, ⊥Department of Biological Chemistry, and #Howard Hughes Medical Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Chao-Yie
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Department of Pharmacology, ∥Comprehensive Cancer Center, ⊥Department of Biological Chemistry, and #Howard Hughes Medical Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Department of Pharmacology, ∥Comprehensive Cancer Center, ⊥Department of Biological Chemistry, and #Howard Hughes Medical Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Department of Pharmacology, ∥Comprehensive Cancer Center, ⊥Department of Biological Chemistry, and #Howard Hughes Medical Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Internal Medicine, §Department of Pharmacology, ∥Comprehensive Cancer Center, ⊥Department of Biological Chemistry, and #Howard Hughes Medical Institute, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D018360:Crystallography, X-Ray; D005456:Fluorescent Dyes; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000138:chemical synthesis / Q000494:pharmacology; D011487:Protein Conformation; D000089804:Shelterin Complex; D054852:Small Molecule Libraries; D034501:Telomere-Binding Proteins / Q000187:drug effects* / Q000235:genetics; D035341:Telomeric Repeat Binding Protein 2 / Q000187:drug effects* / Q000235:genetics; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D005456:Fluorescent Dyes; D010455:Peptides; D000089804:Shelterin Complex; D054852:Small Molecule Libraries; C504753:TERF2 protein, human; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D014230:Triazoles