title: Exploration of backbone space in foldamers containing alpha- and beta-amino acid residues: developing protease-resistant oligomers that bind tightly to the BH3-recognition cleft of Bcl-xL.
abstract: 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 high stability to degradative enzymes could be valuable pharmacological tools for dissection of cell-signaling networks and might ultimately lead to therapeutic 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 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.
authors.affiliation: Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Jack D
authors.initials: JD
authors.lastname: Sadowsky
authors.forename: Justin K
authors.initials: JK
authors.lastname: Murray
authors.forename: York
authors.initials: Y
authors.lastname: Tomita
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D001665:Binding Sites; D001667:Binding, Competitive; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry*; D010447:Peptide Hydrolases / Q000737:chemistry*; D019151:Peptide Library; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D013997:Time Factors; D051020:bcl-X Protein / Q000737:chemistry*
chemical_list: D000596:Amino Acids; C474007:Bax protein (53-86); D010446:Peptide Fragments; D019151:Peptide Library; D011518:Proto-Oncogene Proteins; D051020:bcl-X Protein; D010447:Peptide Hydrolases