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Matrix metalloproteinases (MMPs) are a family of zinc-dependent enzymes that regulate the degradation of the ECM components. Imbalance in their activity might lead to a variety of diseases, including cancer and cardiovascular diseases. As the family of natural tissue inhibitors of metalloproteinases (TIMPs) regulates MMPs activity, they have become an attractive target for therapeutic drug design. Yet, their short circulation half-life makes a serious limitation for this purpose. Therefore, we chose to focus on N-TIMP2 and to apply protein PEGylation in order to increase its size and to extend its circulation half-life. Since the common approaches for protein PEGylation are not site-specific and randomly target amino acids on the target protein, which might affect the protein functionality and stability, we are incorporating a non-canonical amino acid (NCAA), Propargyl lysine (PrK), into N-TIMP2 at different positions, allowing a site-specific PEGylation. Our preliminary results show significant improvements in the pharmacokinetic profile using our new approach.

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Site-specific PEGylation of N-TIMP2 utilizing non canonical amino acids (NCAA) and click chemistry reaction. N-TIMP2 was incorporated with the non-canonical amino acid propargyl lysine (PrK, in blue), that bears an alkyne group, to allow the site-specific conjugation of a PEG-azide molecule via a click chemistry reaction.

Related publications

Bioorthogonal PEGylation Prolongs the Elimination Half-Life of N-TIMP2 While Retaining MMP Inhibition
Hayun H, Arkadash V, Sananes A, Arbely E, Stepensky D, and Papo N. Bioconjugate Chem. 2022


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