Transglutaminase and Sialyltransferase Enzymatic Approaches for Polymer Conjugation to Proteins.

Proteins hold a central role in medicine and biology, also confirmed by the several therapeutic applications based on biologic drugs. Such therapies are of great relevance thanks to high potency and safety of proteins. Nevertheless, many proteins as therapeutics might present issues like fast kidney clearance, rapid enzymatic degradation, or immunogenicity. Such defects implicate frequent administrations or administrations at high doses of the therapeutics, thus yielding or exacerbating potential side effects. A successful technology for improving the clinical profiles of proteins is the conjugation of polymers to the protein surface. The design of a protein-polymer conjugate presents critical aspects that determine the efficacy and safety of the final product. The control over stoichiometry and conjugation site is a strict criterion on which researchers have been intensively focused during the years, in order to obtain homogeneous and batch-to-batch reproducible products. An innovative site-specific conjugation strategy relies on the use of enzymes as tools to mediate polymer conjugation. Enzymatic approaches are attractive because they allow site-selective polymer conjugation at specific protein amino acids. In these reactions, the polymer is a substrate analog that replaces the native substrate. Furthermore, enzymes can count other advantages such as high yields of conversion and physiological conditions of reaction. This chapter provides a meaningful description of protein-polymer conjugation through transglutaminase-mediated and sialyltransferase-mediated enzymatic strategies, reporting the mechanism of action and some relevant examples.

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