Send to

Choose Destination
Chembiochem. 2013 Sep 2;14(13):1564-72. doi: 10.1002/cbic.201300351. Epub 2013 Aug 8.

Structure-guided rational design of α/β-peptide foldamers with high affinity for BCL-2 family prosurvival proteins.

Author information

Department of Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria (Australia).


We have used computational methods to improve the affinity of a foldamer ligand for its target protein. The effort began with a previously reported α/β-peptide based on the BH3 domain of the proapoptotic protein Puma; this foldamer binds tightly to Bcl-x(L) but weakly to Mcl-1. The crystal structure of the Puma-derived α/β-peptide complexed to Bcl-x(L) was used as the basis for computational design of variants intended to display improved binding to Mcl-1. Molecular modelling suggested modification of three α residues of the original α/β backbone. Individually, each substitution caused only a modest (4- to 15-fold) gain in affinity; however, together the three substitutions led to a 250-fold increase in binding to Mcl-1. These modifications had very little effect on affinity for Bcl-x(L). Crystal structures of a number of the new α/β-peptides bound to either Mcl-1 or Bcl-x(L) validated the selection of each substitution. Overall, our findings demonstrate that structure-guided rational design can be used to improve affinity and alter partner selectivity of peptidic ligands with unnatural backbones that bind to specific protein partners.


BH3 domain; Mcl-1; apoptosis; peptide design; peptidomimetics

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center