Design of a Short Thermally Stable α-Helix Embedded in a Macrocycle
Overview
Affiliations
Although helices play key roles in peptide-protein and protein-protein interactions, the helical conformation is generally unstable for short peptides (10-15 residues) in aqueous solution in the absence of their binding partners. Thus, stabilizing the helical conformation of peptides can lead to increases in binding potency, specificity, and stability towards proteolytic degradation. Helices have been successfully stabilized by introducing side chain-to-side chain crosslinks within the central portion of the helix. However, this approach leaves the ends of the helix free, thus leading to fraying and exposure of the non-hydrogen-bonded amide groups to solvent. Here, we develop a "capped-strapped" peptide strategy to stabilize helices by embedding the entire length of the helix within a macrocycle, which also includes a semirigid organic template as well as end-capping interactions. We have designed a ten-residue capped-strapped helical peptide that behaves like a miniprotein, with a cooperative thermal unfolding transition and T ≈70 °C, unprecedented for helical peptides of this length. The NMR structure determination confirmed the design, and X-ray crystallography revealed a novel quaternary structure with implications for foldamer design.
Dual-Capped Helical Interface Mimics.
Mi T, Gao Z, Mituta Z, Burgess K J Am Chem Soc. 2024; 146(15):10331-10341.
PMID: 38573124 PMC: 11027154. DOI: 10.1021/jacs.3c11717.
Bicyclic Schellman Loop Mimics (BSMs): Rigid Synthetic -Caps for Enforcing Peptide Helicity.
Mi T, Nguyen D, Burgess K ACS Cent Sci. 2023; 9(2):300-306.
PMID: 36844493 PMC: 9951308. DOI: 10.1021/acscentsci.2c01265.
Wiedemann B, Kamps D, Depta L, Weisner J, Cvetreznik J, Tomassi S PLoS One. 2022; 17(6):e0267651.
PMID: 35731722 PMC: 9216541. DOI: 10.1371/journal.pone.0267651.
Unprotected peptide macrocyclization and stapling via a fluorine-thiol displacement reaction.
Islam M, Junod S, Zhang S, Buuh Z, Guan Y, Zhao M Nat Commun. 2022; 13(1):350.
PMID: 35039490 PMC: 8763920. DOI: 10.1038/s41467-022-27995-5.
Folding-controlled assembly of -phenylene-based macrocycles.
Kirinda V, Hartley C Chem Sci. 2021; 12(20):6992-7002.
PMID: 34123327 PMC: 8153221. DOI: 10.1039/d1sc01270c.