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Final Report Summary - MICROPEP (Synthetic Polypeptides with Well-Defined Microstructures and Biological Activity)

Peptides are nature's expression language and as such perform vital roles in living organisms. They are highly functional and produced naturally with a precision that is unprecedented in synthetic polymers. Synthetic polypeptides present a promising alternative as they combine the accessibility of synthetic polymers with functionality and biocompatibility of natural peptides. They are thus ideally suited as a new (commercial) renewable and sustainable polymer materials platform if some practical hurdles in polymerization control can be overcome.
In this project, new routes for the synthesis of polypeptides are explored that are inexpensive, scalable and reproducible, and allow the tuning of polypeptide properties by copolymerization. While natural polypeptides are highly complex in structure, this project aims at structurally simplistic yet bioactive synthetic polypeptides.
In the first project phase a methodology was developed for the synthesis of polypeptides with a defined block sequence. This was achieved by the sequential addition of alternating amino acid precursor monomers. A set of polypeptides with identical length and copolymer composition was obtained yet with different amino acid arrangements. Further selective functionalisation of one amino acid with poly(ethylene glycol) converted the materials into amphiphilic copolymers. It was found that depending on the block sequence the solubility as well as the aggregation behaviour varied. This was the first time the importance of sequential arrangement for properties of synthetic polypeptides was demonstrated.
This concept was further exploited for the design of glycopolypeptides with defined positioning of the glycans (sugars) along the polypeptide chain. Carbohydrates (glycans) play an important role in many biological processes, a.o. cell communication, cell-cell recognition, inflammation and fertilization. Synthetic glycopolypeptides are inherently biocompatible and biodegradable and are structural mimics of natural glycoproteins. The production of well-defined glycopolypeptides in larger quantities is still a challenging task and the understanding of their hierarchical assembly is an indispensable condition to a smart design of advanced functional materials. Building on the polymerisation chemistry developed in the first phase of the project a set of glycopolypeptides has been developed comprising the same overall composition yet a different structural arrangement and positioning of the glycans. This includes a random arrangement as well as blocky arrangements of different block length along the polypeptide chain. The sequential arrangement of the glycan units were thus systematically varied, and the influence on the secondary structure and these new materials investigated for their binding to glycan receptors in model reactions with lectins and it was found that the arrangement with the regular short blocks displayed the fasted binding kinetics. The results provide first evidence that spacial arrangements of glycans along a polymer chain may be used to mediate binding to cell receptors. It opens possibilities to design better smart materials for the targeted delivery of active ingredients (e.g. drugs) though glycan mediated receptor binding.

Contact

Laurent Nelissen, (Managing Director)
Tel.: +31 40 247 3000
Fax: +31 40 244 4321
E-mail
Record Number: 196697 / Last updated on: 2017-04-05
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