## 2 Synthetic Approaches for Peptide-Synthetic Polymer Hybrids
### Liquid-Phase Peptide Synthesis. Preparation of Peptide-Synthetic Polymer Hybrids in Liquid-Phase  
_a-N_-carboxyanhydride ring-opening polymerization (_a_-NCA ROP) enables the efficient generation of homopolypeptides or block copolopeptides possessing desired chemical functionality to a targeted molecular weight in a controlled manner. This technique allows multi-gram scale synthesis, but has the disadvantage that NCA's are very sensitive monomers. Thus, polymerizations proceed via multiple competitive chain growth pathways (different initiating sites and termination reactions), which restrict control over polymer architecture as well as molecular weight and molecular weight distribution. Over the past decade new strategies were developed so as to enable the \"living\" behavior of NCA's polymerization. The control over the growing polymer chains was achieved using primary amines orammonium salts, thiol groups and silazines, by means of the use of transition metal complexes based principally on nickel, cobalt and platinum or using high vacuum techniques [14,15]. In spite of the fact that the research on the synthesis of peptide hybrid block copolymers began in the mild 1970s by [PERSON] _et al._[16], this area is constantly under evolution due to its potential to obtain different hybrid peptide-polymer architectures. Recently, [PERSON] _et al._[17], proposed the synthesis of well-defined core-shell molecular bottlebrushes (polydispersity index, PDI, between 1.02 and 1.03) with a helical poly(L-glutamate) backbone and polylactide-\(b\)-poly(ethylene glycol) block copolymer as side chains through the \"_grafling to_\" strategy and using the azide-alkyne Huisgen 1,3-dipolar cycloaddition. These core-shell brushes exhibited a wormlike conformation related to the retention of the \(\alpha\)-helical conformation in both solution and solid state. A related work focused on hybrid peptide-polymer brushes, prepared by means of the \"_grafling through_\" approach (Scheme III) [18], was based on polynorhorene (PN) as backbone with grafted poly(\(\gamma\)-benzyl-L-glutamate) (PBLG) or poly(\(\varepsilon\)-benzyloxycarbonyl-L-lysine) (PLL) as side chains. The selected synthetic methodology led to a small library of polymer brushes with variable PN and peptide lengths and grafting densities. Relevant information related to the helical structure of these complex structures characterized by a high \"local\" concentration of extensive inter-chain interactions was consequently provided. **Scheme III. ** Synthetic approaches based on [18] towards PBLG grafted on a homopolymer backbone of polynorhone (PN-\(g\)-PBLG\({}_{\rm n}\))\({}_{\rm x}\) (**a**), and PBLG grafted on random copolymer backbone of polynorhone (PN-\(g\)-PBLG\({}_{\rm n}\))\({}_{\rm x}\)-\(r\)-PN\({}_{\rm y}\) (**b**). Also addressing control over the polymer architecture, [PERSON] _et al._[19], proposed the \"_grafling from_\" route to obtain a well-defined polymer brush with a narrow molar mass dispersstudy an oligolysine (\(n=8\)) possessing a terminal double bond was employed as macroinitiator to grow methyl methacrylate (MMA) by a conventional radical polymerization that resulted in a PMMA backbone having oligolysine side chains. This molecular brush architecture afforded the short peptide side chains a constrained environment to adopt an enhanced chirality. In this way, the ordered secondary structures of oligopeptides were favored and stabilized. An elegant work based also on polymer brushes was carried out by [PERSON] _et al._[20] by combining the \"_grafting from_\" and the \"_grafting to_\" approaches. This study proposed the synthesis of a pH/temperature sensitive poly(ethylene glycol)-poly(L-alanine) grafted chitosan (CS-g-(PA-PEG)) in two steps. Firstly, an amine-terminated PEG was used as macroinitiator to polymerize alanine NCA and afterwards, reacted with succinin anhydride (SA) to obtain carboxylic acid-terminated PA-PEG chains.