Introduction

Today, to improve naturally occurring biomaterials, material chemists have been developing efficient methods to study biomimetic polymers [1, 2]. Advance materials must be developed to achieve the potential applications in the field of biomaterials science [3, 4]. One class of biomimetic polymer of particular interest is called peptoids, or N-substituted glycines [5] which have found many biomedical applications. Peptoids can be synthesized very efficiently by solid-phase synthesis, and combinatorial libraries were readily produced and screened to afford a novel set of active scaffolds in the early 1990s [6–8] as a modular approach to the discovery of novel drugs [9]. A desirable feature of these biomimetic heteropolymers is that they can be synthesized with defined monomer sequences that resist proteolysis [10–13]. Peptoids have also been shown to have antibacterial properties and clinical promise relative to those of natural peptides [14–17].

Peptoids are polymers of N-substituted glycines and are structural isomers of natural peptides. The side chains are attached to the α-carbon instead of the backbone of amide nitrogen (Fig. 1). They are prepared by the solid-phase submonomer method from primary amines, and their synthesis has been fully automated using simple adaptation of commercial peptide synthesizers [18, 19].

Fig. 1
figure 1

Chemical structure comparison of peptide and peptoid

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Recent reviews on peptoids highlight the scope and applications of highly customizable peptidomimetic macromolecules with many cited references [20–22]. The pioneering works of Bartlett and co-workers in 1992 reported the development of a combinatorial array of N-substituted glycine oligomers by peptidomimetic protocols. So, one can easily notice the booming progress in the development of monomeric scaffolds and this contributed to the exponential development of protected achiral N-substituted glycine monomers.

Background

Peptoid synthesis

The regioisomerization of peptides essentially affords a new class of peptidomimetics, called peptoids [6]. Peptoids are achiral, since the side chains are appended to the amide nitrogen rather than α-carbon. Peptoids of the defined sequence are prepared by the solid-phase “sub-monomer” method, in which bromoacetic acid and N,N′-diisopropylcarbodiimide (DIC) were employed to accomplish the acylation step, followed by nucleophilic displacement of bromine with a primary amine. Consequently, quite diverse polypeptoid sequences can be developed by means of typical primary amines in successful iteration of the displacement reaction step. Rink amide resins are often employed, resulting in the release of peptoid as a C-terminal amide. The final cleavage step is accomplished using trifluoroacetic acid (TFA)-mediated special cocktails [23].

Synthetic strategies for peptoid construction

The technical interest in the developed solid-phase submonomer method by Zuckermann et al. has been significant with automated combinatorial synthetic procedure [7], in which chemically diverse peptoid libraries can be constructed effectively by iterative bromoacetylation and amination reactions. The search for alternative strategies is beneficial to reduce the reaction time and competent yields. This has led to the development of microwave-assisted solid-phase synthesis of peptoids [24–26]. Current synthetic approaches allow for the facile insertion of pendant groups exhibiting various chemical moieties. By the chemical functionality of the side chain moieties, it is quite possible to design peptoid heteropolymers, possessing structural diversity with unique chemical features. Constrained cyclic peptoids are also conformationally designed by efficient submonomer methodology and followed by cyclization in the solution phase [27]. Classic synthesis of cyclic peptoids relies on the simple strategic adaptation of combinatorial chemistry by high-throughput screening of linear peptoids [28]. Alternatively, peptoids are synthesized from solution-phase technique with limited sequential control of <10 residues [29] and, conversely, N-carboxyanhydride (NCA) is a more convenient precursor for peptoids. In this case, high degrees of polymerization can be achieved by ring opening polymerization with low sequence precision control [30–33]. Combinatorial peptoid array has been developed by the photolithographic technique using photolabile synthons for protein binding agents and this anticipated the protein ligand discovery [34]. Surprisingly, biosynthetic protocol involving the synthesis of peptoid–peptide hybrids with linear and cyclic scaffolds was programmed by mRNA and practically reported recently [35].

Customized biomedical applications of peptoids

Bioactive peptoids were discovered by rational design using molecular modeling and developed by either individually or in parallel focused libraries. Peptoids with defined structures seem to possess superior activities and new applications have emerged. The synthesis of hybrid cyclic peptoids has been emphasized in terms of molecular recognition, drug delivery and catalysis. However, solid-state assembly of free and metal coordination provide competing inter-annular hydrogen bond interactions, leading either to a T-shape or to a tubular arrangement of the peptoid macrocycles, and Hirshfeld surfaces and fingerprint plots were generated [36]. The choice of side chain functionalities plays a vital role in the construction of attractive supramolecular architectures. Also, it decides the diverse solid-state properties and conformational flexibility of cyclic α-peptoids [37]. The inter- and intramolecular cyclization of N-(2-aminoethyl)glycine monomers, comprising N-alkyl and N-acyl substituents, affords stable 6- and 12-membered cyclic products. These libraries can be effectively used as potential candidates in enhancing the autophagic degradation of cargo in a live cell model [28, 38]. N-substituted-β-aminopropionic acid oligomers or β-peptoids were initially reported by Hamper et al. [39] by solid-phase methodology. Further, this was preceded by Roy et al. [40] to achieve β-peptoid macrocycles with multimeric ligation of bioactive ligands. Their effective functionalization was achieved by click chemistry synthetic route. Recent advances have begun to address the issue of cyclization methodology to attain macrocyclic peptoids. This has led to the suggestion that head-to-tail macrocyclization and ring closing metathesis approaches were effective for assembling the cyclic peptoids [41, 42]. Based on their relationship with side chain chemistries, Huang et al. suggested that oligomeric peptoids bearing a cationic nature with hydrophobic side chains showed potent antimicrobial activities against Gram-negative Escherichia coli (E. coli), Gram-positive Staphylococcus aureus (S. aureus) and Bacillus subtilis (B. subtilis). Peptoid sequences after head-to-tail macrocyclization mode interestingly showed enhanced antibacterial activity with increasing hydrophobic domains.

A minimum inhibitory concentration (MIC) value of cyclic decapeptide gramicidin S (CGS) for B. subtilis is 2 and 15.6 μg mL−1 for E. coli and S. aureus (see Fig. 2 for chemical structures and Table 1 for MIC values). Moderate activity with MIC <100 μgmL−1 was depicted by L3, L8 and C3. Effective activity was perceived by C8, cyclic peptoid decamer, with MIC values of 0.5 μgmL−1 for B. subtilis, and 7.8 μg mL−1 for E. coli and S. aureus, whereas the linear version of gramicidin S (LGS) showed 7.8 μg mL−1 for B. subtilis and 125 μg mL−1 E. coli and S. aureus [43]. The MIC values are remarkably better than oxazoline-based oligomers (pseudo peptides) and quaternary ammonium/phosphonium polymers [44, 45]. The inherent structural tendency, cellular permeability [46] and multiple binding sites of cyclic peptoids are extremely useful and can be employed for the metal–organic framework (MOF) structures to develop biomimetic materials and three-dimensional solid-state supramolecular assemblies.

Fig. 2
figure 2

Structures of selected linear and cyclic peptides and peptoid sequences [43]

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Table 1 Antimicrobial activities of linear and cyclic peptoids [43]
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Peptoids with more hydrophilicity display the best cell permeability. In addition, peptoids with hydrophobic moieties, usually aromatics, cannot differentiate between the binding domains of different proteins [47]. Kodadek and co-workers comprehensively performed the peptoid cellular permeability criterion. By employing the split-pool method, a library of more than 350 peptoids and α-peptide tetramers was prepared and analyzed to generate structure–property relationships and their relative cell permeability. From the observations, the average cell permeability of the peptoids was twice that of the α-peptides [86]. As shown by the extensive research on the construction of a variety of peptoids, peptoid nucleic acid precursors bearing adenine, guanine and thymine units to nitrogen by flexible ethylene bridge was achieved by the Mitsunobu reaction. The deprotection of these amino acids affords protected dipeptoids [73]. In the recent past, Park and Kwon explored the pharmacokinetic properties of new combinatorial series of linear and cyclic peptoid analogs. Also, they showed the biological activities by blocking the interaction between apolipoprotein E and amyloid-β and proposed these therapeutic peptoid series for the treatment of Alzheimer’s disease [48]. Incorporation of a zinc binding region into the peptoid two-helix bundle was implemented by Zuckermann and colleagues in the early 2008 [49]. Stabilizing characteristics of native protein structures by zinc showed catalytic enzyme cofactor activities, which influenced the choice of zinc-binding motifs. These developed peptoids would only be capable of binding with the zinc, when suitably folded into the helix bundle structure. The thiols and imidazole groups were incorporated into the helical segments of the aforementioned peptoid, expecting the zinc to stabilize the folded state of the two-helix bundles by holding the helical segments in close proximity. The authors analyzed the ability of peptoids to bind with the zinc and the structure alterations in the presence of zinc [50].

Peptoids with heterocyclic pendants show their possible applications in catalysis and materials science. Primary amines derived from imidazole, pyridine and other heterocyclic synthons in the preparation of novel peptoids were gracefully illustrated by the SPOT technique. The SPOT concept was performed on the cellulose membrane strips [51–53]. These heteroaromatic groups that are incorporated act as multidentate ligands in the peptoid chain. These ligands enable their use in metal coordination and are popularly known as metallopeptoids [54]. Maria and Galia [55] suggested that the insertion of the chiral hydrophilic “(S)-(1)-1-methoxy-2-propylamine” group within the peptoid sequences offers water solubility. These water-soluble functional peptoids [56] emphasize their applications in sensors and catalysis. Inevitably, motivation of the significant antiproliferative active peptoids without heteroaromatic side groups showed active cytotoxic efficacy against human neoplastic cell lines [57]. Recently, a compelling approach has been put forward for the stability of nanoparticles under biological assembly conditions using small peptoids [58]. These small peptoids were projected on the development of fluorescent pH sensors. [59].

In contrast to the amino acid derivatives and cyclic dipeptides, “N-alkyl urea peptoids”, as they share some structural similarities with “N-acyl glycine oligomers”, demonstrated the synthesis of soft materials and served as ideal candidates for structure/property relationship studies with peptoids. Organogelators with diverse functional N-alkyl groups afford fiber-like aggregates and can be attained by incorporating ureidopyrimidinone (UPy) group and N-alkyl urea peptoid oligomers into the polymeric gels [60]. The significant work of the Wu and Mangunuru research teams pointed to the importance of peptoid hydrogels. They revealed various protected glucosamine moieties along with aryl functional groups in the peptoid side chains. Also, the self-assembling properties of these new classes of tripeptoids and the in vivo stability of the peptoid–peptide molecular hydrogel conjugates are highlighted [61, 62]. These gelators are extensively studied because of their consolidation properties in tissue engineering and drug delivery applications. The design of specific protein binding to the terminal peptoid sequence proved the formation of polyelectrolyte amphiphiles. These amphiphiles form self-assembly systems and act as nano-sized carriers for lipophilic drug delivery [63, 64].

Nacre mimetic materials are considerably more complicated to synthesize than the synthetics [65]. They form the bio analogs within the fixed dimensions to afford hybrid organic/inorganic composite materials in the order of nanoscale range [66, 67]. The incorporation of calcium carbonate (CaCO3) to both the soluble synthetic polymer films and insoluble hybrid polymeric matrices afford thin solid films. These mineralized films have been demonstrated to be a model for explicative studies on the concept of biomineralization [68–70]. Peptoid nanosheets are highly stable nanoarchitectures with bilayered hybrid structures of thickness ≈3 nm and lateral dimensions varying between few hundreds of micrometers [64, 71]. The use of peptoid-based self-assembling bioinspired nanomaterials have proven to be a reliable approach in the creation of functional and biomimetic materials. Directed assembly process has the potential to develop free-floating two-dimensional nanostructured material sheets [13]. These sheets are formed relatively at lower activation energy. The compression of loop-forming peptoid domains is confined in phases such as air–water or oil–water interphases to assemble into nanosheets (Fig. 3). These fundamental findings gathered interest in designing antibody mimetic peptoid nanosheets [19]. These nanosheets are an emerging class of two-dimensional biomimetic materials with customizable properties.

Fig. 3
figure 3

Imaging of 2D crystalline sheets assembled from periodic amphiphilic peptoid polymers. In typical conditions, 0.1 mM of (Nae–Npe)18 and (Nce–Npe)18 were mixed in Tris–HCl buffer (pH 9.0, 100 mM). a SEM images of sheets on Si substrate. b Height-mode AFM image of a sheet (Z range 20 nm) [64]

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More recently, peptoid nanosheets are mineralized with CaCO3 by plunging the nanosheets in a prescribed concentration of calcium chloride (CaCl2) solution and slowly diffusing carbon dioxide (CO2) into the solution to afford the mineralized nanosheets [71]. It is absolutely vital to explore these fabricated biomimetic materials with specific dimensions for tissue engineering applications [72]. The hydrophilic and zwitterionic surface morphology of these two-dimensional structures make them free-floating suspensions in solution. Due to the exceptional stability of peptoid nanosheets and their ease of surface functionalization, gold-ornamented peptide–peptoid hybrid analogs can be designed [13, 19]. The resulting applications range from clinical to materialistic interests by embedding bioactive nanostructures on these flexible well-defined peptoid nanosheets.

Summary and outlook

Polypeptoids are exemplary non-natural polymers projected to mimic the functions of natural peptides or proteins. These pseudo peptides are tuned structurally to mimic the significant cooperative properties by altering the side chain chemistries and building subunits. Subsequent modification of the alkyne side chain of poly(N-propargyl glycine) can readily serve the modular platform for the production of pseudo peptide ionic liquids and graft copolymers [74, 75]. These bioinspired materials demonstrate a capability for folding, self-assembly and specific biorecognition. In the course of development to get the protein-like properties with narrow polymer molecular weight distributions, helical polymers have been designed by introducing chirality into monomer side chains [76]. Side chain groups with aromatic and heterocyclic moieties [77] are accountable for change in optical activity to target ribonucleic acid (RNA) [78, 79].

Designing the biomimetic polymers for controlled biomineralization is a very challenging task. One way to ease this claim is to develop a peptoid library with the preferred functional side chain groups [72, 80]. Effective pharmacokinetic activity and biological activities with increased resistance to enzymatic degradation is often shown by cyclic peptoids. They possess constrained flexibility compared with the linear ones [48]. Oligopeptoids predominantly composed of “(S)-N-(1-phenylethyl)glycine” residues are generally water insoluble. The flexible hydrophilic carboxy phenylethyl side chains are anticipated to provide both water solubility and structure-inducing elements to form stable helical structures resembling polyproline I type of helix [81, 82]. Peptide–peptoid hybrids (peptomers) with preferred active sites and functional groups specifically activate the melanocortin 4-receptor with improved enzymatic stability and intestinal permeability [83]. Pharmaceutically relevant heterocyclic side chains such as pyridine, pyrazine, imidazole and quinolone pendant moieties can be incorporated efficiently by the SPPS methodology, though the heterocyclic nitrogen containing side chain is present within the peptoid [84].

Today, a variety of peptidomimetic oligomeric scaffolds are being explored to show significant applications ranging from medicinal chemistry to materials science. Researchers are incorporating chemically diverse pendant groups to the peptoid sequence to study the formation of stable self-assemblies and biomimetic folded structures. Sequence specificity has been illustrated by the insertion of clinically bioactive complex heterocycles with variable polysaccharide mimic side chains to afford peptoid combinatorial library for biomedically relevant studies [83, 84]. On the contrary, the applications of peptoid nanoarchitectures have become more prevalent. Peptoid nanosheets and nanotubes have gained great attention recently [13, 19, 71, 87], because it has been realized that the efficacy of these designs provides vast contributions to the biomaterials and biomedical science [88]. Owing to their excellent biocompatibility and biofunctionality, peptoid polymers with specific sequential order have substituted the thought of designing biocompatible implants from the idea of biomimetics [15, 88]. As peptoids display potent antibacterial and antifouling properties [89], these are developed according to clinical needs [16]. To gain insight into the antibiotic properties of the peptoid synthetics, Brauer et al. proposed a design strategy, in which 1,3-diyne-linked peptoids were developed by reliable sequential Ugi-4CR/Glaser coupling approach [90–93].

Polypeptoids are a highly demanding class of biorelevant polymers and have great potential toward biomedical applications [85, 86, 88, 94]. In relation to their peptide predecessors, they promise to be biocompatible and degradable, but yet enzymatically resistant. Fundamental investigations illustrated that polypeptoids undergo phase transformations in response to temperature and have thermo-processability potential [33, 92]. These features would allow the designing of polymer–drug conjugates and composite biomaterials. Furthermore, the functional allyl or propargyl side-chain polypeptoids [75] allow cross-linking and surface modifications, facilitating the design of mechanically strong materials with biologically interacting molecules. In all these pursuits, there are many challenges that need to be overcome and further research is required prior to the targeted design of biomaterials. The fundamental work described herein was driven by the preceding practical prospective of these polymers. Undoubtedly, these developments will help both synthetic and material chemists a great deal in presenting unexplored possible biobeneficial significance.