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Polypeptides one step at a time

Just as polymers are formed from many repeating monomers, polypeptides in nature are synthesised by joining peptides. Novel methodologies have shed light on the mechanisms of synthetic polypeptide formation, promising enhanced control.

Industrial Technologies

Peptides are ubiquitous in cells and form the building blocks of molecules that perform a myriad of functions. The ability to produce synthetic polypeptides with precision mimicking that of nature would be a tremendous tool for synthetic chemistry. It could provide the platform for sustainable and renewable polymer production. Scientists investigated the potential with EU-funding of the project 'Highly functional polypeptides' (HIPEP). They took a specific synthesis reaction of industrial relevance as a case study. N-carboxyanhydride (NCA) ring-opening polymerisation is the most versatile method of synthesising biopolymers. It has great potential for easy production of the next generation of multifunctional polypeptide structures. It successively joins ring-shaped monomers (peptides or short chains of amino acids) containing amino acid NCAs. It is used to make glatiramer, the active ingredient in a prescription pharmaceutical to treat multiple sclerosis. However, lack of detailed knowledge of reaction mechanisms prevents precise control. Scientists first worked on developing a way to identify the individual monomers, not only the presence of amino acid NCAs, in mixtures. The property that makes amino acid NCAs so useful in synthetic chemistry — reactivity — also makes their existence fleeting and difficult to detect. The team developed protocols utilising acid hydrolysis to facilitate their recovery. A method exploiting high-performance liquid chromatography facilitated separation of the different amino acid NCAs and an ultraviolet light detector to detect individual ones. Application of the newly developed methods opened a window with access to extensive kinetic data on the polymerisation of three amino acid NCAs simultaneously. Glatiramer consists of four amino acids. Experimental data were used to predict the behaviour of the ternary system with excellent success. Methodologies developed within the scope of HIPEP pave the way to better prediction of amino acid NCA behaviour during polymerisation. It will enable better control over the amino acid sequence and hence properties of the polymer product. Not only are innovative new polypeptide polymers expected but the technology should also enhance our understanding of the mechanism of action of polypeptide drugs.

Keywords

Polymer, peptide, synthetic polypeptide, N-carboxyanhydride, ring-opening polymerisation, biopolymers, amino acid, glatiramer

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