β-Amino Acids: Versatile Peptidomimetics

Abstract

The use of peptidomimetics has emerged as a powerful means for overcoming the limitations inherent in the physical characteristics of peptides thus improving their therapeutic potential. A peptidomimetic approach that has emerged in recent years with significant potential, is the use of beta-amino acids. Beta-amino acids are similar to alpha-amino acids in that they contain an amino terminus and a carboxyl terminus. However, in beta-amino acids two carbon atoms separate these functional termini. beta-amino acids, with a specific side chain, can exist as the R or S isomers at either the alpha (C2) carbon or the beta (C3) carbon. This results in a total of 4 possible diastereoisomers for any given side chain. The flexibility to generate a vast range of stereo- and regioisomers, together with the possibility of disubstitution, significantly expands the structural diversity of beta-amino acids thereby providing enormous scope for molecular design. The incorporation of beta-amino acids has been successful in creating peptidomimetics that not only have potent biological activity, but are also resistant to proteolysis. This article reviews the rapidly expanding applications of beta-amino acids in the design of bioactive peptide analogues ranging from receptor agonists and antagonists, MHC-binding peptides, antimicrobial peptides and peptidase inhibitors. Given their structural diversity taken together with the ease of synthesis and incorporation into peptide sequences using standard solid-phase peptide synthesis techniques, beta-amino acids have the potential to form a new platform technology for peptidomimetic design and synthesis.

Structural and biological mimicry of protein surface recognition by α/β-peptide foldamers

“…The greater stability of ␣/␤-peptide 10 relative to ␣/␤-peptide 4 likely results from the greater helical propensity of 10, as detected by CD. The small number of proteolysis products observed for ␣/␤-peptide 10 supports previous observations that ␤-residues in mixed ␣/␤ backbones tend to protect neighboring amides from proteolytic cleavage (25,31).…”

“…␣/␤-Peptides 5 and 6 represent an improvement in gp41 mimicry relative to 4 (vide supra), but it would be desirable to place ␤-residues throughout an ␣/␤-peptide sequence to maximize resistance to proteolysis (30)(31)(32). Each ␣3␤ 3 replacement, however, adds a flexible bond to the backbone, which should increase the conformational entropy penalty associated with helix formation (26,33,34).…”

“…When the two bundles are aligned via the NHR trimer (Fig. 3B), the CHR helices track very closely in the C-terminal segment (0.84 Å C ␣ rmsd for residues [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33], but diverge near the N terminus (4.2 Å C ␣ rmsd for residues [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. This divergence reflects a greater superhelical twist in ␣-peptide 3 relative to ␣/␤-peptide 10.…”

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

“…S8A). It has been proposed that the introduction of β-amino acids into the peptides provides increased resistance to hydrolysis and contributes to their stability in biological systems (32,33). Additionally, the gichigamins lack both glutamine (Gln) and glutamic acid (Glu) residues, which Ac U P U P F J…”

“…Each of the new products showed increased potency in PANC-1 cells relative to 1 (SI Appendix, Table S19). The effect was most highly pronounced when aromatic moieties (e.g., phenyl, biphenyl, naphthyl, coumarin, anthracene, and anthraquinone) (33)(34)(35)(36)(37)(38)(39) were introduced. In contrast, the coumarin-linked analog of alamethicin (43) exhibited only a minor increase in potency in PANC-1 cells (GI 50 6.75 μM for alamethicin and GI 50 structural features of the gichigamins were essential to the overall unique biological activity of this group of peptaibols.…”