Synthesis of Peptoids Containing Multiple Nhtrp and Ntrp Residues: A Comparative Study of Resin, Cleavage Conditions and Submonomer Protection

Abstract

Peptoids hold status as peptide-mimetics with versatile biological applications due to their proteolytic stability and structural diversity. Among those that have been studied in different biological systems, are peptoids with dominant balanced hydrophobic and charge distribution along the backbone. Tryptophan is an important amino acid found in many biologically active peptides. Tryptophan-like side chains in peptoids allow H-bonding, which is absent from the parent backbone, due to the unique indole ring. Furthermore, the rigid hydrophobic core and flat aromatic system influence the positioning in the hydrocarbon core and allows accommodating tryptophan-like side chains into the interfacial regions of bacterial membranes and causing bacterial membrane damage. Incorporating multiple tryptophan-like side chains in peptoids can be tricky and there is a lack of suitable, synthetic routes established. In this paper, we investigate the synthesis of peptoids rich in Nhtrp and Ntrp residues using different resins, cleavage conditions, and unprotected as well as tert-butyloxycarbonyl-protected amines suitable for automated solid-phase submonomer peptoid synthesis protocols.

Alternating Cationic‐Hydrophobic Peptide/Peptoid Hybrids: Influence of Hydrophobicity on Antibacterial Activity and Cell Selectivity

“…While Trp is seen as a hydrophobic amino acids, its indole group possesses a substantial dipole moment and an ability to form hydrogen bonds, which might lead to an increased interaction between the Trp residues and the bacterial membrane [35] . In the present series, these unique physicochemical properties of the indole in Trp [36] provide a possible explanation for peptidomimetic 18 exhibiting eightfold higher antibacterial activity against E. coli than peptidomimetic 24 displaying 2‐Nal residues, also having bicyclic aromatic side chains.…”

The Recent Advance of Cell-Penetrating and Tumor-Targeting Peptides as Drug Delivery Systems Based on Tumor Microenvironment

“…37 In terms of hydrophobic CPPs, the hydrophobic fragments have affinity for hydrophobic components in cell membranes, initiating cell internalization. 38 Endocytosis is an energy-requiring process that consists of two different steps, with endocytosis followed by endosome escape. 39 For endocytosis, independent or dependent pathways for caveolae and clathrin have been reported, as well as macropinocytosis.…”

“…Generally, cationic CPPs with positive charges can interact with negatively charged cell membranes to induce membrane destabilization, thereby allowing peptides to enter the cytoplasm . In terms of hydrophobic CPPs, the hydrophobic fragments have affinity for hydrophobic components in cell membranes, initiating cell internalization …”

The Antimicrobial, Antibiofilm and Anti-Inflammatory Activities of P13#1, a Cathelicidin-like Achiral Peptoid

“…As a basic residue we preferred NLys, the peptoid analogue of lysine, over NArg because the use of an NLys residue facilitates the synthetic process; moreover, according to our analysis, in high-scoring peptides, Lys and Arg are equivalent. As an aromatic residue, we selected N-(2-phenylethyl)-glycine (Npet), the peptoid analogue of homophenylalanine, as this residue is slightly more hydrophobic than NPhe (the peptoid analogue of Phe) and is more stable and easier to handle with respect to the peptoid analogues of Trp [45].…”