Polypeptides synthesis, NCAs

Abstract This article summarizes recent developments in the synthesis of polypeptides and hybrid peptide copolymers. Traditional methods used to polymerize -amino acid-N-carboxyanhydrides (NCAs) are described, and limitations in the utility of these systems for the preparation of polypeptides are discussed. Recently developed initiators and methods are also discussed that allow polypeptide synthesis with good control over chain length, chain length distribution, and chain-end functionality. The latter feature is particularly useful for the preparation of polypeptide hybrid copolymers. The methods and strategies for the preparation of such hybrid copolymers are described, as well as analysis of the synthetic scope of the different methods. Finally, issues relating to obtaining these highly functional copolymers in pure form are detailed. 

Fig. 1. Survey of the number of reports describing polypeptide synthesis via NCA ring-opening polymerization. Source. SciFinder Scholar, Dec. 2003.

Template polymerization for polypeptide synthesis was reported by Ballard and Bamford (63) and described in detail in Reference 2. The substrate for the synthesis was V -carboxy-a-amino acid anhydride (NCA). The first step consists in the reaction of NCA with secondary amine on the end of the polypeptide template. The ring-opening process and the elimination of CO2 then proceeds as a chain reaction. Valuable experimental material concerning the polymerization of many different N-carboxyanhydrides initiated by many different polypeptides (64-66) as well as by poly(vinyl pyridine) (67,68) was collected by Imanishi and co-workers. 

Fig. 1 Methods for synthesis of polypeptides via NCA polymerization (a) amine-initiated [13, 14], (b) W-trimethylsilyl-initiated [15-17], and (c) initiated with transition metal complexes. M can be Ni, Co, Fe, Ru, or Ir [18-20]...

Synthetic peptide-based polymers are not new materials homopolymers of polypeptides have been available for many decades, yet have only seen limited use in materials applications. However, new methods in chemical synthesis have made possible the preparation of increasingly complex polypeptide sequences of controlled molecular weight that display properties far superior to ill-defined homopolypeptides. Examination of the different methods for polypeptide synthesis reveals the limitations of these techniques for preparation of well-defined copolymers. Conventional solid-phase peptide synthesis is neither useful nor practical for direct preparation of large polypeptides (> 100 residues) due to unavoidable deletions and truncations that result from incomplete deprotection and coupling steps. The most economical and expedient process for synthesis of long polypeptide chains is the polymerization of a-amino acid N-carboxyanhydrides (NCAs)... 

The application of template ring-opening polymerization for polypeptide synthesis was reported by Ballard and Bamford. " The substrate for the synthesis was N-carboxy-a-amino acid anhydrides (NCA). 

Polypeptide Synthesis Using NCAs 2.1 Conventional Methods... 

Scheme 47 Synthesis of Polypeptides Incorporating Diazobenzene Alanine by the NCA Method 871...

Random polypeptides have traditionally been synthesized by copolymerization of amino acid NCAs. Methods for the synthesis and application of random copolymers have been extensively reviewed (e.g., ref1221), and thus only a single example is given here. A second class of random polypeptides includes organized polymeric assemblies that incorporate bioactive sequences and/or structures. Such polymers have been developed for modulation of protein-ligand interactions/231 protein adsorption to surfaces/241 and cell adhesion/25-281 Several examples for the synthesis of these polymeric assemblies are provided below. 

Deming T.J. Polypeptide and Polypeptide Hybrid Copolymer Synthesis via NCA Polymerization. Vol. 202, pp. 1-18. 

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