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

Naoki Ousaka (), Mark J. MacLachlan () and Shigehisa Akine ()
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Naoki Ousaka: Kanazawa University
Mark J. MacLachlan: Kanazawa University
Shigehisa Akine: Kanazawa University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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 106 and 1012 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.

Date: 2023
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DOI: 10.1038/s41467-023-42493-y

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