α-Helix mimicry with α/β-peptides

Lisa M. Johnson, Samuel H. Gellman

Research output: Chapter in Book/Report/Conference proceedingChapter

78 Scopus citations

Abstract

We describe a general strategy for creating peptidic oligomers that have unnatural backbones but nevertheless adopt a conformation very similar to the α-helix. These oligomers contain both α- and β-amino acid residues (α/β-peptides). If the β content reaches 25-30% of the residue total, and the β residues are evenly distributed along the backbone, then substantial resistance to proteolytic degradation is often observed. These α/β-peptides can mimic the informational properties of α-helices involved in protein-protein recognition events, as documented in numerous crystal structures. Thus, these unnatural oligomers can be a source of antagonists of undesirable protein-protein interactions that are mediated by natural α-helices, or agonists of receptors for which the natural polypeptide ligands are α-helical. Successes include mimicry of BH3 domains found in proapoptotic proteins, which leads to ligands for antiapoptotic Bcl-2 family proteins, and mimicry of the gp41 CHR domain, which leads to inhibition of HIV infection in cell-based assays.

Original languageEnglish (US)
Title of host publicationMethods in Protein Design
PublisherAcademic Press Inc.
Pages407-429
Number of pages23
ISBN (Print)9780123942920
DOIs
StatePublished - 2013

Publication series

NameMethods in Enzymology
Volume523
ISSN (Print)0076-6879
ISSN (Electronic)1557-7988

Keywords

  • Alpha-helix mimicry
  • Alpha/beta-peptides
  • BH3 domain
  • Beta-peptides
  • Foldamers
  • Protein-protein interactions
  • gp41 HIV

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