Stapled β-Hairpins Featuring 4-MercaptoprolineClick to copy article linkArticle link copied!
- Jennifer R. PaceJennifer R. PaceDepartment of Chemistry, Tufts University, Medford, Massachusetts 02155, United StatesMore by Jennifer R. Pace
- Bryan J. LampkinBryan J. LampkinDepartment of Chemistry, Tufts University, Medford, Massachusetts 02155, United StatesMore by Bryan J. Lampkin
- Charles AbakahCharles AbakahDepartment of Chemistry, Tufts University, Medford, Massachusetts 02155, United StatesMore by Charles Abakah
- Adam MoyerAdam MoyerMolecular Engineering and Sciences Institute, University of Washington, Seattle Washington 98195, United StatesMore by Adam Moyer
- Jiayuan MiaoJiayuan MiaoDepartment of Chemistry, Tufts University, Medford, Massachusetts 02155, United StatesMore by Jiayuan Miao
- Kirsten DepreyKirsten DepreyDepartment of Chemistry, Tufts University, Medford, Massachusetts 02155, United StatesMore by Kirsten Deprey
- Robert A. CerulliRobert A. CerulliGraduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, United StatesMore by Robert A. Cerulli
- Yu-Shan LinYu-Shan LinDepartment of Chemistry, Tufts University, Medford, Massachusetts 02155, United StatesMore by Yu-Shan Lin
- James D. BalejaJames D. BalejaGraduate School of Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, United StatesMore by James D. Baleja
- David BakerDavid BakerMolecular Engineering and Sciences Institute, University of Washington, Seattle Washington 98195, United StatesDepartment of Biochemistry, Institute for Protein Design, and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, United StatesMore by David Baker
- Joshua A. Kritzer*Joshua A. Kritzer*[email protected]Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United StatesMore by Joshua A. Kritzer
Abstract

Peptides constrained by intramolecular cross-links, especially stapled α-helices, have emerged as versatile scaffolds for drug development. However, there are fewer examples of similarly constrained scaffolds for other secondary structures. Here, we used a novel computational strategy to identify an optimal staple for antiparallel β-strands, and then we incorporated that staple within a β-hairpin peptide. The hairpin uses 4-mercaptoproline as a novel staple component, which contributes to a unique, kinked structure. The stapled hairpins show a high degree of structure in aqueous solution, excellent resistance to degradation in cell lysates, and cytosolic penetration at micromolar concentrations. They also overlay with a unique subset of kinked hairpin motifs at protein–protein interaction interfaces. Thus, these scaffolds represent promising starting points for developing inhibitors of cellular protein–protein interactions.
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