The natural function of many proteins depends on their ability to switch their conformation driven by environmental changes. In this work, we present a small, monomeric β-sheet peptide that switches between a molten globule and a folded state through Zn­(II) binding. The solvent-exposed hydrophobic core on the β-sheet surface was substituted by a His3-site, whereas the internal hydrophobic core was left intact. Zn­(II) is specifically recognized by the peptide relative to other divalent metal ions, binds in the lower micromolar range, and can be removed and re-added without denaturation of the peptide. In addition, the peptide is fully pH-switchable, has a pK a of about 6, and survives several cycles of acidification and neutralization. In-depth structural characterization of the switch was achieved by concerted application of circular dichroism (CD) and multinuclear NMR spectroscopy. Thus, this study represents a viable approach toward a globular β-sheet Zn­(II) mini-receptor prototype.

The functionalisation of peptides at a late synthesis stage holds great potential, for example, for the synthesis of peptide pharmaceuticals, fluorescent biosensors or peptidomimetics. Here we describe an on‐resin iodination‐substitution reaction sequence on homoserine that is also suitable for peptide modification in a combinatorial format. The reaction sequence is accessible to a wide range of sulfur nucleophiles with various functional groups including boronic acids, hydroxy groups or aromatic amines. In this way, methionine‐like thioethers or thioesters and thiosulfonates are accessible. Next to sulfur nucleophiles, selenols, pyridines and carboxylic acids were successfully used as nucleophiles, whereas phenols did not react. The late‐stage iodination‐substitution approach is not only applicable to short peptides but also to the more complex 34‐amino‐acid WW domains. We applied this strategy to introduce 7‐mercapto‐4‐methylcoumarin into a switchable ZnII responsive WW domain to design an iFRET‐based ZnII sensor.

This report describes the application of cyanosulfurylide (CSY)-protected aspartatic acid building blocks in microwave-assisted synthesis of aggregation-prone protein domains. We present a synthesis of Fmoc-Asp(CSY)-OH on a multigram scale, as...

The three-dimensional structure of a peptide, which determines its function, can denature at elevated temperatures, in the presence of chaotropic reagents, or in organic solvents. These factors limit the applicability of peptides. Herein, we present an engineered β-hairpin peptide containing a His 3 site that forms complexes with Zn II , Ni II , and Cu II . Circular dichroism spectroscopy shows that the peptideÀ metal complexes exhibit melting temperatures up to 80 °C and remain folded in 6 M guanidine hydrochloride as well as in organic solvents. Intrinsic fluorescence titration experiments were used to determine the dissociation constants of metal binding in the nano-to subnanomolar range. The coordination geometry of the peptideÀ Cu II complex was studied by EPR spectroscopy, and a distorted square planar coordination geometry with weak interactions to axial ligands was revealed. Due to their impressive stability, the presented peptideÀ metal complexes open up interesting fields of application, such as the development of a new class of peptideÀ metal catalysts for stereoselective organic synthesis or the directed design of extremophilic β-sheet peptides.

Aminoboronsäuren sind pharmakologisch wichtige Wirkstoffe, die beispielsweise gegen Krebs, Bakterien oder Entzündungen wirken. Das Interesse an effizienten Synthesestrategien ist daher groß. Aktuelle Methoden fokussieren sich auf regio‐ und stereoselektive Borylierungen sowie die direkte Funktionalisierung durch C‐H‐Aktivierung.