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Template-assisted enzymatic synthesis of oligopeptides from a polylactide chain
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology.
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Polymer Technology. University of Sannio, Italy.
KTH, School of Biotechnology (BIO), Protein Technology. (Protein engineering of enzymes)
KTH, School of Biotechnology (BIO), Protein Technology. (Protein engineering of enzymes)
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2017 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 18, no 12, p. 4271-4280Article in journal (Refereed) Published
Abstract [en]

Peptides are often attached to polymer materials, as bioactive components, for the control of interactions between the material and its surrounding proteins and cells. However, synthesizing peptides and attaching them to polymers can be challenging and laborious. Herein, we describe the grafting of oligopeptides to an aliphatic polyester, using a one-step chemo-enzymatic synthesis with papain as the biocatalySt. To enable enzyme-mediated functionalization of the polyester, ethyl hept-6-enoylalaninate (grafter) was synthesized and attached to polylactide chains using thiol-ene click reactions. The oligopeptides were grafted onto the polylactide chains using two different synthetic routes: the grafting from strategy, in which the grafter was attached to the polyester prior to oligopeptide synthesis, or the grafting to strategy, in which oligopeptides were synthesized on the grafter first, then attached to the polymer chain. The final products were analyzed and their structures were confirmed using nuclear magnetic resonance (NMR). The peptide attachment was evaluated using size exclusion chromatography (SEC), contact angle measurement and energy-dispersive X-ray spectroscopy scanning electron microscopy (EDS-SEM). Furthermore, the mechanistic aspects of the synthesis of the oligopeptides on the grafter were studied using molecular dynamics (MD) simulations. The simulation revealed that hydrogen bonding (between the P1 amide nitrogen of the grafter backbone and the carbonyl oxygen of D158 in the papain) maintain the grafter in a productive conformation to stabilize the transition state of nitrogen inversion, a key step of the biocatalytic mechanism. Apart from being biologically relevant, both experimental and computational results suggest that the designed grafter is a good template for initiating chemo-enzymatic synthesis. The results also showed that the grafting to strategy was more successful compared to the grafting from strategy. Overall, a successful synthesis of predefined peptide functionalized polylactide was prepared, where the oligopeptides were grafted in an easy, time efficient, and environmentally friendly way.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017. Vol. 18, no 12, p. 4271-4280
Keywords [en]
Polymer synthesis, Polylactide, Peptide functionalization, Chemo-enzymatic synthesis
National Category
Polymer Technologies
Research subject
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-219562DOI: 10.1021/acs.biomac.7b01315ISI: 000418109200040PubMedID: 29131581Scopus ID: 2-s2.0-85038214474OAI: oai:DiVA.org:kth-219562DiVA, id: diva2:1163597
Funder
Swedish Research Council, 2013-3764VINNOVAEU, FP7, Seventh Framework Programme, 291795
Note

QC 20171211

Available from: 2017-12-07 Created: 2017-12-07 Last updated: 2018-01-12Bibliographically approved
In thesis
1. Synthesis of degradable aliphatic polyesters: strategies to tailor the polymer microstructure
Open this publication in new window or tab >>Synthesis of degradable aliphatic polyesters: strategies to tailor the polymer microstructure
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Key factors for successful tissue engineering are the synthesis and design of the scaffold materials. Aliphatic polyesters have been studied and often used as scaffold materials for tissue engineering. However, their lack of biological cues and degradation under high-temperature processing (e.g., 3D printing) are a limitation. In this thesis, different synthesis strategies are presented which has the potential to improve the performance of aliphatic polyesters as scaffolds for tissue regeneration.

To stimulate interactions between exogenous materials and the surrounding tissue, two different strategies were applied. Either, by designing a two component system in which the different degradation profiles of the polymers allow for sequential release of growth factors. Or, by peptide functionalization of an aliphatic polyester chain using template-assisted chemo-enzymatic synthesis. The results from the studies were successful. A hierarchical system was obtained in which the poly(L-lactide-co-glycolide)-graft-poly(ethylene glycol) methyl ether (PLGA-g-MPEG), hydroxyapatite solution formed a gel around and within the pores of the poly(L-lactide-co-ε-caprolactone) scaffold at 37 ºC, within 1 min, that was stable for 3 weeks. The peptide functionalization was also successful where an aliphatic polyester of L-lactide was functionalized with different oligopeptides using a grafter (ethyl hept-6-enoylalaninate) and chemo-enzymatic synthesis.

The thermal properties of poly(L-lactide-co-hydroxybutyrate) were tailored (by modification of the microstructure) to potentially improve the processability of the aliphatic polyester.  The results showed that the yttrium salan catalyst was the most successful, yielding high molecular weight copolymers in shorter time. They also showed that the Tg could be tailored by varying the amount of rac-β-butyrolactone in the copolymer to better suit thermal processing techniques, such as 3D printing.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2018. p. 78
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2017:35
Keywords
Polymer synthesis, enzymatic synthesis, degradable polyesters, peptides, scaffolds
National Category
Polymer Technologies
Research subject
Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-219550 (URN)978-91-7729-615-7 (ISBN)
Public defence
2018-01-15, F3, Lindstedtsvägen 26, Stockholm, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 2013-3764
Note

QC 20171207

Available from: 2017-12-07 Created: 2017-12-07 Last updated: 2017-12-07Bibliographically approved

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