Julius-Maximilians-Universität Würzburg, Germany
Click Functionalization of Peptides and Proteins: New Tools for Inorganic Chemical Biology
Bioorthogonal reactions for covalent modification of bio(macro)molecules, in particular peptides and proteins, are so far mostly a domain of bioorganic chemistry [1,2]. However, introduction of metal-based functionalities also hold great promise for applications in Inorganic Chemical Biology, e.g. by exploration of metal-inherent properties such as rich photophysics, electrochemical bistability, tunable ligand-exchange kinetics, and availability of stable as well as radioactive isotope markers. In that context, our group develops novel chemistry to quickly generate molecular diversity in metal complex-bio(macro)molecule conjugates. In this presentation, two different and novel approaches will be discussed and their scope and limitation critically assessed.
The first methodology is based on the [3+2] cycloaddition of a metal-azide complex and an alkyne coupling partner directly in the inner metal coordination sphere [3-5]. A particular highlight is the formation of very robust triazolate linkers under retention of the stereochemistry, without a catalyst, and at room temperature that are stable in aqueous solution for at least several months, as demonstrated by ESI mass spectrometry. A systematic overview across the d-block elements will be given together with kinetic data, including the trapping of intermediates at low temperature (-20 °C), which revealed 2nd order rate constants comparable to the Staudinger ligation reaction well-established in bioorganic chemistry [1-2].
In addition, first mass spectrometric data will be presented on a novel “indole conjugation”, in which organometallic indole conjugates are covalently attached to lysine sidechains of proteins under retention of the native protonation state .