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Bulletin of the Korean Chemical Society (BKCS)

ISSN 0253-2964(Print)
ISSN 1229-5949(Online)
Volume 35, Number 12
BKCSDE 35(12)
December 20, 2014 

Effective α-Helix Stabilization via Hexenyl Propionate Cross-Link
Jiyeon Yoo, Young-Woo Kim*
α-Helix, Stapled peptides, Ring-closing metathesis, Hexenyl propionate, Peptide drugs
In this study we examined two ester-containing cross-links, hex-2-enyl acetate and hex-2-enyl propionate, as new cross-linking systems for helix stabilization of short peptides. We demonstrated that these hexenyl ester cross-links can be readily installed via a ruthenium-mediated ring-closing metathesis reaction of L-aspartic acid 4-allyl ester or L-glutamic acid 5-allyl ester at position i and (S)-2-(4'-pentenyl)alanine at position i+4 using second generation Hoveyda-Grubbs catalyst at 60 oC. Between these two cross-links, we found that the hex-2- enyl propionate significantly stabilizes the α-helical conformations of short model peptides. The helixstabilizing effects of the hex-2-enyl propionate tether appear to be as powerful as Verdine’s i,i+4 allhydrocarbon stapling system, which is one of the most widely used and the most potent helix-stabilizing crosslinking systems. Furthermore, the hex-2-enyl propionate bridge is reasonably robust against non-enzymatic hydrolytic cleavage at a physiological pH. While extended studies for probing its chemical scopes and biological applications are needed, we believe that this new helix-stabilizing system could serve as a useful chemical tool for understanding protein folding and designing conformationally-constrained peptide drugs.
3627 - 3631
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