A Field Guide to Optimizing Peptoid Synthesis

Abstract

N-Substituted glycines (peptoids) are a class of peptidomimetic molecules used as materials for health, environmental, and drug delivery applications. Automated solid-phase synthesis is the most widely used approach for preparing polypeptoids, with a range of published protocols and modifications for selected synthetic targets. Simultaneously, emerging solutionphase syntheses are being leveraged to overcome limitations in solid-phase synthesis and access high-molecular weight polypeptoids. This Perspective aims to outline strategies for the optimization of both solid-and solution-phase synthesis, provide technical considerations for robotic synthesizers, and offer an outlook on advances in synthetic methodologies. The solid-phase synthesis sections explore steps for protocol optimization, accessing complex side chains, and adaptation to robotic synthesizers; the sections on solution-phase synthesis cover the selection of initiators, side chain compatibility, and strategies for controlling polymerization efficiency and scale. This text acts as a "field guide" for researchers aiming to leverage the flexibility and adaptability of peptoids in their research.

Rational Design of Novel Peptidomimetics against Influenza A Virus: Biological and Computational Studies

“…In the solid-phase synthesis of peptoid, there are two distinct methods to introduce a N -alkylglycine (peptoid residue) on the growing peptide chain: (i) the N-substituted glycine derivative, appropriately protected at the tertiary nitrogen atom, can be prepared distinctly and used as a building block in the solid-phase procedure (monomer method) [ 43 , 44 ], or, alternatively, (ii) the peptoid residue is created during the growing peptide chain by combining two submonomers, a haloacetic acid and a primary amine (submonomer approach) [ 35 ].…”

Cysteine Redox Chemistry in Peptide Self-Assembly to Modulate Hydrogelation

“…They consist of poly( N -substituted glycine), whereby the variable residues on the nitrogen atom can mimic amino acid sidechains, with the net advantage of added resistance against protease-mediated hydrolysis [ 74 ]. They are typically produced by solid-phase methods, but also in liquid phase, and their synthesis is continuously being optimized to the benefit of researchers interested in their use [ 75 ]. However, their altered ability to engage in H-bonds, relative to peptide analogs, can lead to a reduced ability to form hydrogels [ 76 ].…”

Nano-topography and functionalization with the synthetic peptoid GN2-Npm9 as a strategy for antibacterial and biocompatible titanium implants

“…Peptoids have a high degree of specificity due to their unique structure [ 7 , 8 ]. Currently, the synthesis of peptoids is complex and time-consuming but strategies for controlling the processes’ efficiency and scale are proceeding quickly [ 9 ].…”