5-Hydroxy-pyrrol-2-one based building blocks as maleimide alternatives for protein bioconjugation

In recent years, there has been a significant increase in the use of proteins for several commercial applications such as therapeutics, packaged foods and even household products. For this purpose, natural proteins require modification to improve their shelf-life, pharmacokinetic properties and bioavailability. From all 20 natural amino acids, cysteine is the ideal amino acid for chemo- and regioselective modification in proteins due to its low natural abundancy and the nucleophilicity of the sulfhydryl group (pKa~8). Thiol-maleimide conjugation is the most often used strategy today for cysteine selective modification. Nonetheless there are several drawbacks related to maleimides including hydrolysis of the maleimide building blocks, retro-Michael reaction and thiol exchange. The OBCR lab at UGent has gathered considerable expertise in furan based chemistry and its applications for DNA and peptide cross-linking, peptide labelling, peptide-protein and DNA-protein conjugation. Combining the successful results in both areas in order to further broaden the scope of furan-based reactions, we propose the development of 1-(R2)-5-hydroxy-5-(R1)-1,5-dihydro-2H-pyrrol-2-one (5HP2O) building blocks as maleimide alternatives for protein bioconjugation. They can easily be synthesized via a one-pot photo-redox reaction using methylene blue as photosensitizer. Combining different furans and amines enables generation of a diversified series of building blocks with two property enhancing groups (R1, R2). We successfully conjugated our building blocks to a series of thiol containing model compounds.

The technology described is part of a pending patent application: filing number EP 19160048.5.

Authors

Ewout De Geyter (1), Abhishek Iyer (1), Eri Antonatou (1), Sabina Smolen (1), Dimitris Kalaitzakis (2), Georgios Vassilikogianakis (2), An Van Den Bulcke (3), Annemieke Madder (1)

Organisations

"(1) Organic and Biomimetic Chemistry Research group, Ghent University, Krijgslaan 281 S4, B-9000 Ghent, Belgium, (2) Department of Chemistry, University of Crete, Vasilika Vouton, 71003, Iraklion, Crete Greece, (3) UGent ChemTech Life Science, Ghent University, Krijgslaan 281 S4, B-9000 Ghent, Belgium"

Presenting author

An Van Den Bulcke, Business Developer ChemTech Life Sciences, Ghent University
an.vandenbulcke@ugent.be
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