## 2 Synthetic Approaches for Peptide-Synthetic Polymer Hybrids
### Liquid-Phase Peptide Synthesis. Preparation of Peptide-Synthetic Polymer Hybrids in Liquid-Phase
Concretely, the technique consisted in using polystyrene (PS) beads loaded with amino-terminated poly(ethylene glycol) (PEG) through an acid labile benzyl-ether linker [40; 41; 42; 43; 44]. Subsequently, SPPS was successfully conducted with high efficiency from PEG according to the so-called \"_divergent approach_\" or alternatively a selected pre-formed peptide was chemically linked to the synthetic polymer chain giving rise to the \"_convergent approach_\". Both methodologies were able to liberate the peptide-PEG block copolymer by a subsequent cleavage of the ether linker. A recent example of the use of these pre-loaded resins is the preparation of a peptide-polymer block copolymer in which a \(\beta\)-sheet forming peptide (\(\beta\)A\(\beta\)AKLVFF) was attached to a hydrophilic PEG chain (3000 g/mol) supported on a resin. Specifically, a PEGylated TentaGel PAP resin was used and the peptide was assembled from the \(C\)-terminus towards the \(N\)-terminus. Attachment of the peptide to the solid support at the \(C\)-terminal was achieved through the \(a\)-carboxyl group of the amino acid. The obtained hybrid molecules were able to self-assemble into micelles comprising a modifiedamyloid peptide core surrounded by a PEG corona. The modified amyloid peptide was able to form helical ribbons based on a \(\beta\)-sheet motif and contained \(\beta\)-amino acids that were excluded from the \(\beta\)-sheet structure, thus being potentially useful as fibrillization inhibitors. In the model peptide-PEG hybrid system, the enzymatic degradation using R-chymotrypsin led to selective cleavage close to the PEG-peptide linkage, breaking up the micelles, and releasing peptides in unassociated form. This concept has considerable potential in the targeted delivery of peptides for therapeutic applications [45]. Unfortunately, only resins pre-loaded with PEG are commercially available, and the range of molecular weights is limited. For this reason, other strategies are being nowadays more exploited so as to achieve higher structural versatility. A recent work carried out by [PERSON] _et al._[46], reported a straightforward route to a peptide-synthetic polymer hybrid by means of the synthesis of a protected peptide by automatic SPPS containing a terminal initiating for nitroxide-mediated polymerization (NMP) of styrene (Scheme VII). After trifluoracetic acid cleavage the peptide-polystyrene copolymer was obtained. The NMP polymerization of styrene was controlled on changing the time. In this way, the molar mass could be tuned resulting in macromolecules with a molecular weight ranging from 20,500 to 25,000 g/mol and with a polydispersity index between 1.22 and 1.32. **Scheme VII. ** Strategy of preparation of SG1-functionalized resin peptide for the initiation of nitroxide-mediated polymerization (NMP); (Prot)peptide: GGGW(Boc)IK(Boc)VAV, with the \(N\)-Boc-protected Lysine and Tryptophan (M = 1099 g/mol); Peptide: GGGWIKVAV (M = 885 g/mol) based on [46]. One of the mostly employed strategies is based on the synthesis of peptide-polymer hybrids by using a functionalized peptide, synthesized by SPPS, and performing a \"_grafing from_\" by employing the peptide as a macroinitiator in bulk or solution. For example, [PERSON] _et al._[47], have recently proposed the synthesis of ABC block copolymers by growing two different polymer chains, poly(oligo(ethylene glycol)) methyl ether methacrylate (pOEGMA) and the thermosensitive block of poly(\(N\)-isopropylacrylamide) (pNIPAm), from a native peptide using atom transfer radical polymerization (ATRP). Specifically, these two different ATRP initiators were coupled via orthogonal methods to the \(N\)- and \(C\)-terminus of the peptide Ser-Gly-Pro-G In-Gly-Ile-Phe-Gly-Gln-Met-Gly, a substrate for matrix metalloproteases. Above the cloud point of one of the blocks, the polymers self-assembled into micelles, which were organized with the hydrophilic block on their outer side.