A Conformationally Stable Acyclic β‐Hairpin Scaffold Tolerating the Incorporation of Poorly β‐Sheet‐Prone Amino Acids

Abstract

The β‐hairpin is a structural element of native proteins, but it is also a useful artificial scaffold for finding lead compounds to convert into peptidomimetics or non‐peptide structures for drug discovery. Since linear peptides are synthetically more easily accessible than cyclic ones, but are structurally less well‐defined, we propose XWXWXpPXK(/R)X(R) as an acyclic but still rigid β‐hairpin scaffold that is robust enough to accommodate different types of side chains, regardless of the secondary‐structure propensity of the X residues. The high conformational stability of the scaffold results from tight contacts between cross‐strand cationic and aromatic side chains, combined with the strong tendency of the d‐Pro‐l‐Pro dipeptide to induce a type II′ β‐turn. To demonstrate the robustness of the scaffold, we elucidated the NMR structures and performed molecular dynamics (MD) simulations of a series of peptides displaying mainly non‐β‐branched, poorly β‐sheet‐prone residues at the X positions. Both the NMR and MD data confirm that our acyclic β‐hairpin scaffold is highly versatile as regards the amino‐acid composition of the β‐sheet face opposite to the cationic−aromatic one.

Synthesis and Hydrogelation of Star-Shaped Graft Copolypetides with Asymmetric Topology

“…Upon grafting the functional group, the PLL segment would undergo coil-to-sheet conformational transition, due to the multiple interactions between the functional group. The results are in a good agreement with those reported in the previous studies [ 31 , 32 , 33 ]. As shown in Table 1 , the percentage of β-sheet/β-turn conformations (50.0–60.0%) was much higher than the molar ratio of the functional groups grafted onto the star-shaped polypeptides.…”

Stereochemistry-Driven Interactions of α,γ-Peptide Ligands with the Neuropeptide Y Y4-Receptor

“…The CD spectra of the α,γ-peptides 2a and 2b , which contain γ-CBAA at positions 32 and 34, maintain the same shape both in the absence and presence of TFE, while the intensity of the CD signal changes slightly ( 2b ) or moderately ( 2a ). This indicates that TFE does not induce a conformational transition but, rather, further stabilizes the structure already partially formed (Figure C). , Therefore, the two higher γ-substituted analogues of UR-KK236, especially 2b , display a more rigid and, consequently, less environment-dependent structure.…”

Impact of β-perfluoroalkyl substitution of proline on the proteolytic stability of its peptide derivatives

“…1A). [10][11][12][13] Therefore, a set of eight CF 3 -and C 2 F 5 -substituted stereochemically pure Pro-Gly dipeptides 2a and b were synthesized for the subsequent plasma stability study (Fig. 3).…”

“…1A). [10][11][12][13] Another known possibility to achieve β-turn or β-hairpin structures is to introduce an L-Pro-Gly motif or its D-Pro-Gly analog. [14][15][16] Apart from being a prominent building block for peptides and proteins, proline has become a common motif in synthetic small molecule drugs and biotherapeutics.…”

“…1A). 10–13 Another known possibility to achieve β-turn or β-hairpin structures is to introduce an l -Pro–Gly motif or its d -Pro–Gly analog. 14–16…”