Polypeptoids and Peptoid–Peptide Hybrids by Transition Metal Catalysis

Abstract

Peptoids have attracted attention for application in biomedicine due to their advantageous properties as compared to peptides. The structural analogues are typically resistant to protease degradation and offer improved biocompatibility. Chemical routes to an impressive variety of short-chain, low-molecular-weight peptoids are well-established. However, synthetic methods for well-defined, high-molecular-weight polypeptoids with side chain diversity are still in their infancy. Here, we report a facile method for synthesis of polypeptoids via transition-metal-catalyzed controlled, living polymerization of N-substituted N-carboxyanhydrides. Our method is amenable to hydrophilic and hydrophobic side chains and yields high-molecular-weight linear polypeptoids of predictable length and low dispersity. Further, the polymer end groups can be tuned for biological targeting, and polypeptide-polypeptoid hybrids are readily prepared in one pot. Our materials are indeed resistant to common proteases and are well-tolerated by human cells. Overall, this work represents a significant stride toward access to tunable polypeptoids.

Principles of glycocalyx engineering with hydrophobic-anchored synthetic mucins

“…Using our previously established methods, we synthesized a panel of synthetic mucins (synMUCs) via polymerization of amino acid N -carboxyanhydrides (NCAs) ( Figure 1B ) ( Kramer et al, 2015 ; Clauss et al, 2021 ; Clauss and Kramer, 2021 ; Detwiler et al, 2021 ). Though a variety of molecules have been explored as artificial mucins, we chose our structures due to the fact they are composed entirely of amino acids and sugars found in mucin glycoproteins, contain native linkages, and take on the natural polyproline (PP) II helical conformation that is characteristic of mucins ( Kramer et al, 2015 ; Detwiler et al, 2021 ; Deleray and Kramer, 2022 ).…”

“…PPro was selected since it adopts the stiff PPII helical structure of mucins but does not bear glycans ( Detwiler et al, 2021 ). PSar was selected since, like PPro, it is hydrophilic and non-ionic ( Clauss and Kramer, 2021 ). However, PSar is disordered and flexible in conformation.…”

Advance in Hybrid Peptides Synthesis

“…Until recent years, the preparation of random peptide/peptoid hybrid polymer through controlled polymerization methods had been reported, and the enzymatic degradation behavior of such polymers was studied. [60][61][62] Polypeptides were typically prepared by ring-opening polymerization of 𝛼-NCAs or 𝛼-amino acid N-thiocarboxyanhydrides (𝛼-NTAs), [84,103,104] while polypeptoids were prepared by ring-opening polymerization of N-substituted 𝛼-amino acid N-carboxyanhydrides (𝛼-NNCAs) [10,[105][106][107] or N-substituted 𝛼-amino acid N-thiocarboxyanhydrides (𝛼-NNTAs) [108][109][110] . All above monomers have similar fivemembered cyclic anhydride structures, of which the carbonyl carbon at position 5 on the monomer rings can act as an active site for nucleophilic attack during the initiation and propagation steps through either activated monomer mechanism (AMM) or normal amine mechanism (NAM).…”

“…Several living polymerization methods have been developed though achieving control over the sequence through polymerization methods still remains a challenge. [59][60][61][62][63][64] This review will focus on the development in the synthesis of 𝛼/𝛽peptides and peptide/peptoid hybrids, especially new polymerization methods (Figure 1). Moreover, the future development of polymerization methods to prepare poly-𝛼/𝛽-peptides and peptide/peptoid hybrid polymer with controlled or even defined sequence will be briefly discussed.…”

Exploring the potential of polypeptide–polypeptoide hybrid nanogels for mucosal delivery

“…Moreover, a lead candidate was selected for further drug delivery and mucus penetration studies. Considering recent efforts in the synthesis of functional polypeptoides, [54][55][56] the strategy presented here could open an avenue for the design of biocompatible surface functional nanogels difficult to achieve by other techniques.…”