An Organometallic Chemistry Approach to Peptide Tricycles

Herein, we demonstrate how Au(III) organometallic chemistry offers the potential to streamline the generation of constrained peptide tricycles. By leveraging the chemoselectivity and ultrafast kinetics of tetrametallic Au(III)-based aryl reagents towards cysteine (Cys) bioconjugation, we have constructed a small library of constrained peptide tricycles. These tricycles can be synthesized and isolated in 25-55% yields from various tetracysteine containing linear peptides. In all cases, tricyclization conversion occurs quantitatively under five minutes at sub-mM concentrations of the target peptide and proceeds under varied distributions of the four Cys residues in the target peptide sequence. Furthermore, by constraining various linear peptides around the aryl core of tetraphenylethylene, a common solid-state luminogen, we generate fluorescent macrocycles with robust solution-state emissive profiles. We evaluated the innate affinity of these fluorescent hybrid peptides toward cells, finding they behave as highly selective luminogenic cell markers of cellular debris.