N-Aminoglycine and Its Derivatives Stabilize PPII Secondary Structure

Abstract

The identification of unnatural residues that stabilize polyproline type 2 (PPII) folds can aid in the design of peptidomimetics targeting PPII-binding domains. Here, we examine the impact of peptide backbone N-amination on PPII helix stability and find N-aminoglycine (aGly) to be an effective PPII promoter. Further derivatization of an aGly-containing peptide affords N′-alkylated analogues with increased helical propensity. Backbone N-amination of glycine represents a convenient approach to stabilize PPII conformation and allows for the diversity-oriented synthesis of optimally constrained folds.

Beyond N-Alkylation: Synthesis, Structure, and Function of N-Amino Peptides

“…Additionally, the electron-withdrawing hydrazide N′H 2 group lowers the amide rotational barrier, enhances carbonyl electrophilicity, and therefore lowers the π* CO LUMO energy . Consistent with these characteristics, we found that the incorporation of aGly into a host–guest model peptide enhanced PPII helicity and thermal stability relative to those of both Gly and Pro, as measured by CD (Figure B,C) . In contrast, the PPII fold was severely disrupted when the Cα-substituted aAla was incorporated as the guest residue.…”

“…R. Rajewski, B. H. Wright, M. M. Gerrein, T. A. Del Valle, J. R. 10.1021/acs.orglett.3c0150220232543664370 …”

“…As a result, acylated piperazic acid residues exhibit enhanced trans rotamer bias and lower rotational barriers relative to tertiary amides such as proline. This repulsive effect is maintained at physiological pH since the hydrazide N′ in NAPs is only weakly basic (conjugate acid p K a ≈ 1–3). , The steric imposition of an amide substituent also increases ϕ and ψ rotational barriers and favors A , strain-minimized conformations. Hydroxamate OH and hydrazide N′H 2 groups may engage in H-bonds as donors or acceptors, thus leading to diverse and interchangeable modes of conformational restriction.…”

Enhanced EphB2-Specific Peptide Inhibitors through Stabilization of Polyproline II Helical Structure

“…Similar to lactam cross-linked variants, the trans -2-butenyl cross-linked variant 19 has lower cross-linker hydrophobicity overall and displayed no apparent digestion within 4 h. These data suggest that stability to trypsin proteolysis is independent of EphB2 receptor inhibitory potency. Improvements in proteolytic stability are thus potentially achievable with amide modification, such as N-alkylation or N-amination. , …”

“…The core principle of our approach was to introduce a cross-linker to stabilize the receptor-bound peptide structure in a similar fashion to previous studies. − Specifically, we sought to stabilize the polyproline II helix structure at the C-terminus of SNEW. Factors influencing polyproline II helix stability have been studied extensively in proline-rich peptides, including several examples of cross-linking. − Complementary to these studies, we used the wealth of existing knowledge about cross-linking of peptide α-helices to rationally guide the screening of cross-linkers for stabilization of a single turn of the C-terminal polyproline II helical segment of SNEW . Through design, synthesis, and evaluation of a collection of SNEW variants, we identified variants that are more potent than SNEW in inhibiting the EphB2–ephrin B2 interaction.…”