α-Helix mimicry with α/β-peptides

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.

Figure 19.1

Crystal structures: (A) the β-peptide 14-helix (ACHC hexamer; CSD ID: REF-PUN01; Appella, Christianson, Karle, et al., 1999), (B) the β-peptide 12-helix (ACPC hexamer; CSD ID: WELMAB; Appella, Christianson, Klein, et al., 1999), (C) the α/β-peptide 11-helix (1:1 α/β octamer; alternation of ACPC and Ala or Aib residues; CSD ID: OGATUM; Choi, Guzei, Spencer, & Gellman, 2008), (D) the α/β-peptide 14/15-helix (1:1 α/β decamer; alternation of ACPC and Ala or Aib residues; CSD ID: OGAVEY; Choi et al., 2008), and (E) α-Amino acid residue and several types of β-amino acid residues.

Figure 19.2

Three examples of β-peptides designed to form globally amphiphilic helices: (A) 14-helical (3 residues per turn) cholesterol uptake inhibitor (Werder et al., 1999), (B) 14-helical antimicrobial peptide (Hamuro et al., 1999), and (C) 12-helical (2.5 residues per turn) antimicrobial peptide (Porter et al., 2000).

Figure 19.3

Helix bundles formed by α-peptide GCN4-pLI (A) (PDB ID: 1GCL; Harbury et al., 1993) and three α/β-peptide homologues with varying backbone patterns: (B) ααβαααβ (PDB ID: 2OXK), (C) ααβ (PDB ID: 3C3G), and (D) αααβ (PDB ID: 3C3F). Each image is based on a crystal structure. α Residues are shown in yellow, and β³ residues are shown in blue. Backbone overlays between the α peptide GCN4-pLI and (E) ααβαααβ, (F) ααβ, and (G) αααβ homologues (Horne, Price, et al., 2008).

Figure 19.4

(A) α/β-Peptides with side chain sequences derived from the Puma BH3 domain (1 and 2) or the Bim BH3 domain (3a-b, 4, and 5). The standard single-letter code is used; letters covered with a blue dot indicate β³-homologues of the α residue designated by the letter. Compounds 1, 2, and 3a-b feature the ααβαααβ backbone repeat, while 4 and 5 have the αααβ backbone repeat. (B) Helical wheel diagram of the Puma BH3 domain with the four key hydrophobic residues and the key Asp in bold. The smaller helix-wheel diagrams show how the stripe of β³ residues shifts incrementally around the helix periphery among the seven different versions of the ααβαααβ backbone repeat (Horne, Boersma, Windsor, & Gellman, 2008); the asterisk (*) indicates the α/β registry found in Puma-derived α/β-peptides 1 and 2. (C–E) Images illustrating the complexes between the BH3 domain-derived α- or α/β-peptides (α-residues are yellow, β residues are blue) and Bcl-x_L (light purple): (C) Bak BH3 domain (NMR structure; PDB ID: 1BLX; Sattler et al., 1997); (D) α/β-peptide 2 (crystal structure; PDB ID: 2YJ1; Lee et al., 2011); (E) α/β-peptide 4 (crystal structure; PDB ID: 4A1W; Boersma et al., 2012).

Figure 19.5

α- and α/β-Peptides related to gp41. The color scheme key for the β residues in the sequences is shown at the right: blue for β³ residues and peach for cyclic β residues. Crystal structures: (A) gp41-5 shown in gray ribbon cartoon (PDB ID: 3O3X; Johnson et al., 2011); (B) 6-helix bundle formed by α-peptides T-2635 (yellow) and N36 (gray) (PDB ID: 3F4Y; Horne et al., 2009); (C) α/β-peptide 6 (yellow for α residues, blue for β residues) bound to gp41-5 (gray) (PDB ID: 3O42; Johnson et al., 2012); (D) α/β-peptide 7 (yellow for α residues, blue and peach for β residues) bound to gp41-5 (gray) (PDB ID: 3O43; Johnson et al., 2011).