Synthesis of Functional Polypeptides and Development of New Synthetic Strategies toward Polypeptides

Abstract

The objective of this work is to develop a new synthetic strategy for synthesizing advanced functional polypeptides or polypeptides in general. Polypeptides are amino acids based polymers with appealing properties for different applications. One of the key challenges in polypeptide research is the synthesis of functional polypeptides under mild conditions. We developed a system based on ring-opening polymerization (ROP) of N-thiocarboxyanhydrosulfides (NTAs) to synthesize polypeptides with wide range of molecular weights under mild conditions. Owing to NTAs’ good stability, our system serves as an excellent alternative to the traditional ROP of N-carboxyanhydrides (NCA). In Chapter 1, the fundamental knowledge and the cutting-edge research of polypeptides will be reviewed. The focus of the work in Chapter 2 is to develop a new class of functional polypeptide in traditional method via ROP of NCAs. This class of polypeptides combines several desired attributes for biomedical applications, which include: clickable pendant side chains for further functionalization, good water solubility, non-ionic nature to avoid unspecific interactions in biological systems, and unique secondary conformations (e.g. α-helix, β-sheet). In Chapter 3, I developed the first system to prepare polypeptides with controlled molecular weight via primary amine initiated solid-phase ring-opening polymerization (sROP) of NTAs under mild conditions in open air. Model NTA (e.g. BLG NTA, LYS NTA) monomers were synthesized for the first time, and were found to possess better thermal and moisture stability as compared to NCA analogs. The sROP proceeds by a normal amine mechanism as evidenced by matrix assisted light desorption ionization time of flight mass spectroscopy (MALDI-TOF MS). The controlled polymerization behavior of sROP is the direct result of high local monomer concentration in the solid phase, thus allowing for faster polymerization under relatively mild conditions. The work in Chapter 4 focuses on the development of solution phase polymerization of NTAs with TMG/benzoic acid as co-initiation system. PBLG with high molecular weights (33.6 kg/mol - 66.7 kg/mol) and narrow molecular weight distribution (PDI < 1.12) can be readily prepared with this system. The mechanism of the TMG/benzoic acid mediated ROP of NTAs is proposed to be activated monomer mechanism (AMM).