Peptide design using α,β‐dehydro amino acids: From β‐turns to helical hairpins

Abstract

Incorporation of alpha,beta-dehydrophenylalanine (DeltaPhe) residue in peptides induces folded conformations: beta-turns in short peptides and 3(10)-helices in larger ones. A few exceptions-namely, alpha-helix or flat beta-bend ribbon structures-have also been reported in a few cases. The most favorable conformation of DeltaPhe residues are (phi,psi) approximately (-60 degrees, -30 degrees ), (-60 degrees, 150 degrees ), (80 degrees, 0 degrees ) or their enantiomers. DeltaPhe is an achiral and planar residue. These features have been exploited in designing DeltaPhe zippers and helix-turn-helix motifs. DeltaPhe can be incorporated in both right and left-handed helices. In fact, consecutive occurrence of three or more DeltaPhe amino acids induce left-handed screw sense in peptides containing L-amino acids. Weak interactions involving the DeltaPhe residue play an important role in molecular association. The C--H.O==C hydrogen bond between the DeltaPhe side-chain and backbone carboxyl moiety, pi-pi stacking interactions between DeltaPhe side chains belonging to enantiomeric helices have shown to stabilize folding. The unusual capability of a DeltaPhe ring to form the hub of multicentered interactions namely, a donor in aromatic C--H.pi and C--H.O==C and an acceptor in a CH(3).pi interaction suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures.

Effect of the ΔPhe residue configuration on a didehydropeptides conformation: A combined CD and NMR study

“…The results obtained for the methyl esters, measured in CDCl 3 and DMSO-d 6 , are shown in Table III. They confirm the presence of two hydrogen bonds in Z-OMe, formed by amide protons of Gly 3 and Phe 4 , and indicate the absence of a hydrogen bond in E-OMe. Such studies were not performed for the p-nitroanilides due to their poor solubility in chloroform.…”

“…These conclusions were confirmed by the NMR studies on Z-OMe. They show the presence of two intramolecular hydrogen bonds, formed by the amide protons of Gly 3 and Phe 4 (Tables II and III). The dihedral angles of successive residues of Z-OMe (Table V) indicate that these hydrogen bonds stabilize two overlapping β-turns, of type II at Gly 1 and ∆ Z Phe 2 and type III' at ∆Phe 2 and Gly 3 .…”

“…The most studied dehydroamino acid residue has been dehydrophenylalanine. It has been found that in the solid state a ∆Phe residue of the Z configuration induces β-turns in short sequences [2][3][4][5][6] and a 3 10 -helix in longer ones or peptides with more than one dehydro residue. 4,[7][8][9][10][11][12][13][14][15][16][17][18][19] Similar conformational properties of ∆ Z Phe have been observed in solution by NMR 8,11,[19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] and CD, 18,19,[27][28][29][30][31][32][33][34][35]…”

“…Few crystal structures of ∆ E Phe-containing peptides show that this residue occupies CHCl 3 -ethyl acetate (9:1, v/v)/hexane. Yield 0.247 g (92%); mp 100-102°C; elemental analysis calcd (%) for C 28 4 and ∆ E Phe 2 ; C β H ∆ E Phe 2 ); 8.69 (1H, broad s, NH ∆ E Phe 2 ).…”

Rationale-Based, De Novo Design of Dehydrophenylalanine-Containing Antibiotic Peptides and Systematic Modification in Sequence for Enhanced Potency

“…The presence of more than one ⌬Phe in peptides has been shown to constrain the peptide in a 3 10 or ␣-helical conformation, along with providing enhanced resistance to enzymatic degradation compared to their phenylalanine-containing counterparts (23,29). We used a de novo-designed prototype undecapeptide peptide (VS1) incorporating ⌬Phe as a lead in an optimization strategy to design three sets of peptides with the same basic motif, where ⌬Phe is placed at two residue spaces.…”