Synthetic helical peptide capping strategies

Abstract

Peptidic helix mimics may be formed by “stapling” mid-helix side chains, or “capping” termini so hydrogen bond donors and acceptors there are satisfied. This review considers the differences between them and the potential areas for future development.

Bicyclic Schellman Loop Mimics (BSMs): Rigid Synthetic C-Caps for Enforcing Peptide Helicity

“…7,8 Strategies for designing helical peptidomimetics may feature stapling and N-and C-capping. 9 Many stapling methods have been investigated in depth, 10,11 and studies on N-cap mimics are common. 9,12,13 However, as far as we are aware, only two papers 14,15 mention synthetic C-cap mimics, and both comprise monocyclic rings.…”

“…Strategies for designing helical peptidomimetics may feature stapling and N - and C -capping . Many stapling methods have been investigated in depth, , and studies on N -cap mimics are common. ,, However, as far as we are aware, only two papers , mention synthetic C -cap mimics, and both comprise monocyclic rings. The first incorporated a 1,3-xylene linker between residue C 3 and C″ at the helix C -terminus with moderate helix-inducing effect, and the other is a dual-capped peptide (Figure e).…”

Conjugation as a Tool in Therapeutics: Role of Amino Acids/Peptides-Bioactive (Including Heterocycles) Hybrid Molecules in Treating Infectious Diseases

“…The free C- and/or N-terminal peptides are naturally vulnerable to all kinds of protease enzymes by restricting their in vivo curative potential and finally limiting their usage [ 56 , 57 , 60 ]. The approach of utilising a terminal capping group capable of terminating helices is a successful strategy to minimise the peptide bond sensitiveness towards proteolytic cleavage, thereby enhancing the affinity [ 61 ].…”

Comprehensive Peptide Cyclization Examination Yields Optimized APP Scaffolds with Improved Affinity toward Mint2

“…However, linear peptide fragments serving as starting points for the development of PPI modulators generally suffer from low binding affinity, susceptibility to proteases and limited secondary structure in solution, rendering them suboptimal templates for peptide-based drug discovery. Stabilizing the secondary structure of a peptide fragment is considered a suitable strategy to address certain caveats of peptides, methods include the incorporation of salt bridges, metal chelating groups, and helix-nucleating moieties . Alternatively, macrocyclization of peptides by covalently cross-linking the side chains of two amino acid residues, also referred to as stapling , offers great potential .…”

“…Stabilizing the secondary structure of a peptide fragment is considered a suitable strategy to address certain caveats of peptides, 2 methods include the incorporation of salt bridges, 3 metal chelating groups, 4 and helix-nucleating moieties. 5 Alternatively, macrocyclization of peptides by covalently cross-linking the side chains of two amino acid residues, also referred to as stapling, offers great potential. 6 This methodology is frequently employed in peptide drug discovery, 7 as macrocyclization can convey secondary structure, but has also been reported to improve the metabolic stability 8 and cell permeability 9 of peptide leads (Figure 1a).…”