Toward industrial scale-up of polypeptide synthesis: analysis of monomer suitability

Abstract

Polypeptide is a class of biopolymers that mimic the structure and properties of natural proteins, which makes it fitting for biological applications. The biodegradability and biocompatibility from the peptide backbones combined with the tunability from synthetic chemistry allow for long-chain polypeptides to function for drug delivery, tissue grafting, and gene therapy. Currently, long-chain polypeptides (≥100 amino acids) are not synthesized on a commercial scale (>100 kg.) Based on the potential applications, the optimization of polypeptide production should be discussed at the current stage. Since the majority of the polypeptide synthesis depends on the production of monomer and the polymerization of the monomer into polypeptides, choosing the most suitable monomer for industrial application is critical in designing a polypeptide production line. Based on an industrial standpoint, the ideal monomer should be synthesized conveniently, stored and transported easily, and polymerized efficiently. This article aims to compare and examine the four major groups of monomers used in a laboratory setting: protect amino acid, N-carboxyanhydride (NCA), N-thiocarboxyanhydride (NTA), and N-phenoxycarbonyl-functionalized α-amino acid (NPCA) based on the industrialization criteria stated above, using past experimental results. In the end, NPCA proves to be the most suitable monomer for industrial purposes. Like NCA, NPCA can be synthesized efficiently and can be polymerized into a diverse collection of polypeptides both based on conjugation and structure. Like NTA, NPCA can be synthesized and stored in an open-air environment. Still, NPCA has disadvantages in polymerization efficiency, requiring multiple days for long-chain polymers. Potentially, by increasing the leaving group conjugated to the amino acid, improvement can be made to the polymerization efficiency.