Stapled ß-Hairpins Featuring 4-Mercaptoproline.
J Am Chem Soc
; 143(37): 15039-15044, 2021 09 22.
Article
en En
| MEDLINE
| ID: mdl-34516087
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 ß-strands, and then we incorporated that staple within a ß-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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MEDLINE
Asunto principal:
Péptidos
/
Prolina
Idioma:
En
Revista:
J Am Chem Soc
Año:
2021
Tipo del documento:
Article