Journal
CHEMBIOCHEM
Volume 8, Issue 8, Pages 903-916Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.200600546
Keywords
foldamers; helical structures; parallel synthesis; peptidomimetics; protein-protein interactions
Funding
- NIGMS NIH HHS [5 T32 GM08349, GM56414] Funding Source: Medline
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Protein-protein interactions play crucial roles in cell-signaling events and are often implicated in human disease. Molecules that bind tightly to functional protein-surface sites and show hgih stability to degradative enzymes could be valuable pharmacological tools for dissection of cell-signaling networks and might ultimately lead to thereapeutic agents. We recently described oligomers containing both alpha- and beta-amino acid residues that bind tightly to the BH3 recognition site of the anti-apoptotic protein Bcl-x(L). The oligomers with the highest affinity had a nine-residue N-terminal segment with a 1:1 alpha:beta residue repeat and a six-residue C-terminal segment containing exclusively proteinogenic alpha-residues. The N-terminal portions of such (alpha/beta + alpha)-peptides are highly resistant to proteolysis, but the C-terminal alpha-segments are susceptible. This study emerged from efforts to modify the alpha-segment in an (alpha/beta + alpha)-peptide in a way that would diminish proteolytic degradation but retain high affinity for Bcl-x(L). Some of the oligomers reported here could prove useful in certain biological applications, particularly those for which extended incubation in a biological milieu is required.
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