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 language | English (US) |
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Title of host publication | Methods in Protein Design |
Publisher | Academic Press Inc. |
Pages | 407-429 |
Number of pages | 23 |
ISBN (Print) | 9780123942920 |
DOIs | |
State | Published - 2013 |
Externally published | Yes |
Publication series
Name | Methods in Enzymology |
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Volume | 523 |
ISSN (Print) | 0076-6879 |
ISSN (Electronic) | 1557-7988 |
Bibliographical note
Funding Information:This work was supported by NIH grants GM056414 and GM061238. L. M. J. was supported in part by an NIH Chemistry-Biology Interface Training Grant (T32 GM008293).
Keywords
- Alpha-helix mimicry
- Alpha/beta-peptides
- BH3 domain
- Beta-peptides
- Foldamers
- Protein-protein interactions
- gp41 HIV