Catalyst-free "click" reactions for the direct conjugation of metal complexes to bio(macro)molecules

• Applicant: Professor Dr. Ulrich Schatzschneider
• Subject Area: Biological and Biomimetic Chemistry ; Inorganic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246278426

The mild and site-selective modification of biomacromolecules like peptides and proteins with non-natural functional groups is a significant challenge due to the multitude of reactive groups these compounds present. At the same time, such hybrid systems offer great promise as tools to study fundamental biological processes and they might also find interesting applications in medical diagnosis and therapy. Bioorthogonal "click reactions" like the copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC) are now heavily utilized to introduce new functionalities to biomacromolecules. However, the application of the CuAAC and other coupling methods in living systems is hampered by the need for a potentially toxic transition metal catalyst.Therefore, it is the aim of the present project to develop novel mild and catalyst-free methods for the conjugation of functional metal complexes to peptides and proteins. However, in contrast to other very recent bioorthogonal coupling reactions like the strain-promoted azide-alkyne cycloaddition, our work will be specifically based on a metal-inherent reactivity. At the core of our strategy will be the direct reaction of substitutionally inert metal azides with alkyne-functionalized biomacromolecules in an "iClick reaction" to form a metal-triazolate linkage. Facile variation of the metal center and coligand sphere will allow us to tune the electronic and steric properties of the coupling partners to ensure fast reaction kinetics and introduce a wide variety of functionalities to probe biological systems.The hybrid metal complex-peptide bioconjugates prepared this way will then be studied for stability of the triazolate linkage in challenge experiments with common cellular constituents like amino acids, nucleotides, and biogenic thiols. While initial work will focus on the use of simple model peptides, their complexity will then subsequently be increased to larger carrier peptides of potential biological relevancy. Selected metal complex-peptide hybrids will be tested for their biological activity on human cancer cells.With an established set of metal reaction partners and coupling conditions at hand, this project will then take initials steps towards the modification of functional proteins using the "iClick" reactivity to introduce novel, metal-based functionality to these systems.

• DFG Programme: Research Grants