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Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α-Helix Mimics.

Abstract：

:We report progress toward a general strategy for mimicking the recognition properties of specific α-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both α- and β-amino acid residues, with the density of the β subunits low enough that an α-helix-like conformation can be adopted but high enough to interfere with protease activity. Previous studies with a different protein-recognition system that suggested ring-constrained β residues can be superior to flexible β residues in terms of maximizing α/β-peptide affinity for a targeted protein surface. Here, we use mimicry of the 18-residue Bim BH3 domain to expand the scope of this strategy. Two significant advances have been achieved. First, we have developed and validated a new ring-constrained β residue that bears an acidic side chain, which complements previously known analogues that are either hydrophobic or basic. Second, we have discovered that placing cyclic β residues at sites that make direct contact with partner proteins can lead to substantial discrimination between structurally homologous binding partners, the proteins Bcl-xL and Mcl-1. Overall, this study helps to establish that α/β-peptides containing ring-preorganized β residues can reliably provide proteolytically resistant ligands for proteins that naturally evolved to recognize α-helical partners.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Peterson-Kaufman KJ,Haase HS,Boersma MD,Lee EF,Fairlie WD,Gellman SH

doi

10.1021/acschembio.5b00109

subject

Has Abstract

pub_date

2015-07-17 00:00:00

pages

1667-75

issue

7

eissn

1554-8929

issn

1554-8937

journal_volume

10

pub_type

杂志文章

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