Exploration of α/β/γ-peptidomimetics design for BH3 helical domains

Systematic incorporation of ring-constrained beta- and gamma-amino acid residues into alpha-helix mimetics engenders stable helical secondary structures. In this paper, functional alpha/beta/gamma-helical peptidomimetics were explored for mimicry of BH3 helical domains, Bim as a pioneering study. The Bim-based alpha/beta/gamma-peptides in an alpha gamma alpha alpha beta alpha-hexad repeat with five helical turns inhibited the interaction between Bak and Bcl-x(L) with excellent resistance towards proteolytic digestion. Further optimization of the alpha/beta/gamma-backbone strategy will considerably expand the utility of functional alpha/beta/gamma-peptidomimetics, in particular due to its prominent stability against proteolysis.

Automated summary

The systematic incorporation of ring-constrained beta- and gamma-amino acid residues into alpha-helix mimetics results in stable helical secondary structures. The constructed alpha/beta/gamma-helical peptidomimetics effectively mimic BH3 helical domains and exhibit excellent resistance against proteolytic digestion. Further optimization of the alpha/beta/gamma-backbone strategy is expected to significantly enhance the utility of functional alpha/beta/gamma-peptidomimetics, particularly due to their notable stability against proteolysis.