Protein-Inorganic Array Construction: Design and Synthesis of the Building Blocks

Herein we describe the design and synthesis of the first series of di‐functional ligands for the directed construction of inorganic‐protein frameworks. The synthesized ligands are composed of a metal‐ion binding moiety (terpyridine‐based) conjugated to an epoxysuccinyl peptide, known to covalently bind active cysteine proteases through the active‐site cysteine. We explore and optimize two different conjugation chemistries between the di‐functionalized metal‐ion ligand and the epoxysuccinyl‐containing peptide moiety: peptide‐bond formation (with limited success) and CuI‐catalysed click chemistry (with good results). Further, the complexation of the synthesized ligands with FeII and NiII ions is investigated: the di‐functional ligands are confirmed to behave similarly to the parent terpyridine. As designed, the peptidic moiety does not interfere with the complexation reaction, in spite of the presence of two triazole rings that result from the click reaction. ES‐MS together with NMR and UV/Vis studies establish the structure, the stoichiometry of the complexation reactions, as well as the conditions under which chemically sensitive peptide‐containing polypyridine ligands can undergo the self‐assembly process. These results establish the versatility of our approach and open the way to the synthesis of di‐functional ligands containing more elaborated polypyridine ligands as well as affinity labels for different enzyme families. As such, this paper is the first step towards the construction of robust supramolecular species that cover a size‐regime and organization level previously unexplored. Im Folgenden beschreiben wir das gezielte Design und die Synthese di‐funktionaler Liganden zum erstmaligen Aufbau supramolekularer Metall‐Protein‐Hybridarchitekturen. Die synthetisierten Liganden enthalten eine Metallionen‐Bindungsstelle (auf Terpyridin‐Basis), die mit einem Epoxysuccinyl‐Peptid konjugiert wurde. Diese Peptide binden bekannterweise an die aktiven Cysteine im katalytischen Zentrum von Cystein‐Proteasen. Wir untersuchen und optimieren zwei verschiedene Arten chemischer Konjugations‐Systeme zwischen den di‐funktionalen Metallionen‐Liganden und dem Epoxysuccinyl‐enthaltenden Peptidrest: Bildung einer Peptid‐Bindung (mit geringem Erfolg) und CuI‐katalysierte click Chemie (mit signifikantem Erfolg). Wie beabsichtigt, erfolgt die Komplexierung von FeII‐ und NiII‐Ionen an den synthetisierten Liganden hochselektiv am Terpyridylrest und nicht an den Triazol‐Ringen d