Polypeptoids, a class of peptidomimetic polymers, have emerged at the forefront of macromolecular and supramolecular science and engineering as the technological relevance of these polymers continues to be demonstrated. The chemical and structural diversity of polypeptoids have enabled access to and adjustment of a variety of physicochemical and biological properties (eg, solubility, charge characteristics, chain conformation, HLB, thermal processability, degradability, cytotoxicity and immunogenicity). These attributes have made this synthetic polymer platform a potential candidate for various biomedical and biotechnological applications. This review will provide an overview of recent development in synthetic methods to access polypeptoid polymers with well-defined structures and highlight some of the fundamental physicochemical and biological properties of polypeptoids that are pertinent to the future development of functional materials based on polypeptoids. | I N TR ODU C TI ONPolypeptoids composed of N-substituted polyglycine backbones are structural mimics of polypeptides ( Figure 1). Because of N-substitution, polypeptoids lack stereogenic centers and hydrogen bonding interactions along the main chains, in sharp contrast to polypeptides.As a result, the global conformations of polypeptoids are strongly dependent on the N-substituent structures, giving rise to random coils or well-defined secondary structures [eg, polyproline I (PPI) helix [1][2][3][4][5][6] and R-sheets] [7][8][9][10][11][12] that are reminiscent of those of polypeptides. The polypeptoid backbone containing tertiary amide linkages is highly polar and hydrophilic. The physicochemical properties of polypeptoids can be tailored by the N-substituent structures, enabling control over the hydrophilicity and lipophilicity balance (HLB), charge characteristics, [13,14] backbone conformation, [1][2][3][4][5][6][7][8][9][10][11][12] solubility, [15][16][17][18][19][20] thermal and crystallization properties of the polypeptoids. [21][22][23][24] Without extensive hydrogen bonding, polypeptoids are thermally processable similar to conventional thermoplastics, [20][21][22][23][24] whereas polypeptides undergo thermal degradation before they can be melt-processed due to the extensive hydrogen bonding interactions. While polypeptoids exhibited enhanced proteolytic stability relative to peptides, [25,26] they can be oxidatively degraded under conditions that mimic tissue inflammation, [27] suggesting their potential in vivo uses as biodegradable materials.Recent advances in the controlled polymerization methods have enabled access to a suite of structurally well-defined polypeptoids with various N-substituent structures and molecular architectures, setting the stage for the future development of polypeptoid materials for various targeted applications. Several review articles on the synthesis, properties, and application of polypeptoids for biomedical or nonbiomedical uses have been published in recent years. [28][29][30][31][32] As a result, this...

Interfacial ring-opening polymerizations (iROP) of α-amino-acid derived N-thiocarboxyanhydrides (NTAs) in hexanes or heptane suspension using soluble primary amine initiators have been demonstrated to produce polypeptides with controlled molecular weight and low-tomoderate molecular weight distribution under mild conditions. The NTA monomers were shown to have significantly enhanced moisture and thermal stability relative to Ncarboxyanhydrides (NCAs), resulting in long shelf life and allowing the polymerization to occur quantitatively in open air.

N-Butyl N-carboxyanhydride (Bu-NCA) was polymerized in THF to produce poly(N-butylglycine) using benzyl alcohol initiator and 1,1,3,3-tetramethylguanidine (TMG) promoter. Poly(N-butylglycine) species (PNBG) with controlled molecular weight (M n = 2.9−20.5 kg mol −1 ) and narrow molecular weight distribution (PDI = 1.04−1.08) were obtained by controlling the initial monomer-to-initiator ratio and conversion. The reaction exhibits characteristics of a living polymerization, as evidenced by the linear increase of M n with conversion and successful chain extension experiments. Kinetic studies revealed a first-order dependence of propagation rate on the monomer and benzyl alcohol concentration and zero-order dependence on the TMG concentration, consistent with a controlled polymerization where the TMG does not influence the chain propagation. It was further revealed that the polymerization activities and M n control are strongly dependent on the structure of the alcohol initiators. Primary alcohols (e.g., methanol, ethanol, 2-methoxyethanol, npropanol, and benzyl alcohol) can mediate the polymerization of Bu-NCA with the TMG present to produce PNBG polymers with good to moderate control of M n s and PDIs. By contrast, sterically hindered secondary or tertiary alcohols (e.g., isopropyl alcohol and tert-butyl alcohol) or a primary alcohol bearing strongly electron withdrawing substituents (e.g., 2,2,2trifluoroethanol) or phenol either failed to initiate the polymerization or produced PNBGs whose molecular weights deviated to varying extents from the theoretical values based on single-site initiation with alcohols. 1 H NMR analysis revealed hydrogen bonding interactions between TMG and various alcohols, thereby promoting the initiation by enhancing the nucleophilicity of the alcohols toward ring-opening addition of Bu-NCA monomer. Electron-rich primary alcohols can initiate the polymerization more efficiently than the electron-deficient primary alcohol or sterically hindered secondary or tertiary alcohols, resulting in enhanced control over polymer molecular weight in the former than the latter. The polymerization has been successfully extended toward the synthesis of heteroblock copolymers based on poly(ethylene glycol) (PEG) and PNBG by using a hydroxylended PEG macroinitiator and TMG promoter.

Non-ionic water-soluble helical polypeptides bearing reactive side chains can be efficiently modified with hydrophobic or hydrophilic moieties to produce water-soluble conjugates.