Stapling strategy for slowing helicity interconversion of α-helical peptides and isolating chiral auxiliary-free one-handed forms.

Autor: Ousaka N; Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. ousaka@staff.kanazawa-u.ac.jp., MacLachlan MJ; Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. mmaclach@chem.ubc.ca.; Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada. mmaclach@chem.ubc.ca.; Quantum Matter Institute, University of British Columbia, 2355 East Mall, Vancouver, BC, V6T 1Z4, Canada. mmaclach@chem.ubc.ca., Akine S; Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. akine@se.kanazawa-u.ac.jp.; Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, 920-1192, Japan. akine@se.kanazawa-u.ac.jp.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Oct 26; Vol. 14 (1), pp. 6834. Date of Electronic Publication: 2023 Oct 26.
DOI: 10.1038/s41467-023-42493-y
Abstrakt: In nature, α-helical peptides adopt right-handed conformations that are dictated by L-amino acids. Isolating one-handed α-helical peptides composed of only achiral components remains a significant challenge. Here, this goal is achieved by optical resolution of the corresponding racemic (quasi-)static α-helical peptide with double stapling, which effectively freezes the interconversion between the right-handed (P)- and left-handed (M)-α-helices. An as-obtained doubly stapled analogue having an unprotected L-valine residue at the C-terminus transforms from a kinetically trapped (M)-α-helix to a thermodynamically stable (P)-α-helix upon heating. In contrast, the corresponding singly stapled α-helical peptide undergoes an acid/base-triggered and solvent-induced reversible inversion of its preferred helicity within minutes. The interconversion rates of the singly and doubly stapled α-helical peptide foldamers are approximately 10 6 and 10 12 times slower, respectively, than that of a non-stapled dynamic helical peptide. Therefore, the enantiopure doubly-stapled (quasi-)static α-helical peptide would retain its optical activity for several years at 25 °C.
(© 2023. The Author(s).)
Databáze: MEDLINE
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