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)|
|Title of host publication||Methods in Protein Design|
|Publisher||Academic Press Inc.|
|Number of pages||23|
|State||Published - 2013|
|Name||Methods in Enzymology|
Bibliographical noteFunding 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).
- Alpha-helix mimicry
- BH3 domain
- Protein-protein interactions
- gp41 HIV