Tolcapone

Tolcapone, a clinically approved drug for the treatment of Parkinson’s disease as an adjunct therapy, has recently emerged as a potential modulator of amyloid‐β aggregation and toxicity, which are hallmark features of Alzheimer’s disease and are also involved in ocular neurodegenerative disorders, including glaucoma and age‐related macular degeneration. Despite these noteworthy findings, the molecular basis of the interaction between amyloid‐β and tolcapone remains poorly understood, and the mechanisms by which tolcapone affects metal–amyloid‐β species have yet to be explored. In this work, we investigate the binding interactions of tolcapone with both copper‐free amyloid‐β and copper‐associated amyloid‐β complexes, using a combination of techniques including UV–vis spectroscopy, circular dichroism, mass spectrometry, and surface plasmon resonance. The results reveal that tolcapone binds directly to amyloid‐β monomers. Furthermore, in vitro assays confirm the capacity of tolcapone to act as a radical scavenger and to compete with amyloid‐β for the binding of copper ions. Altogether, our findings suggest that tolcapone exerts a multifaceted protective effect, potentially inhibiting toxic metal‐free and metal aggregation pathways by preventing metal coordination to amyloid‐β or disrupting preformed amyloid‐β–metal complexes, thus offering new perspectives to explore and develop its analogs for the treatment of neurodegenerative disorders.

The notorious pathogen Pseudomonas aeruginosa relies on the lectin LecA for host cell adhesion, invasion, and biofilm formation. Motivated by the pressing need for new anti‐infective therapies caused by antimicrobial resistance, inhibitors of LecA are under investigation. Complementary to the use of carbohydrate‐based inhibitors, we have previously identified catechols as weak but specific ligands of LecA, constituting a novel class of non‐carbohydrate glycomimetics. By growing the initial millimolar fragment hits, we identified Tolcapone as a promising compound. To gain insight into the structure‐activity relationship (SAR) of catechols as LecA binders, more than 3,200 compounds of the Roche in‐house library were experimentally screened in a competitive binding assay at three concentrations. Of these, 48 compounds were chosen for further investigation, resulting in compounds equipotent to aryl galactosides, the current epitome of LecA inhibition. X‐ray crystallography and saturation transfer difference (STD) NMR spectroscopy revealed conserved interactions of the catechol moiety in the glycan binding site of LecA and rationalized the observed SAR. Our findings demonstrate that it is possible to develop potent non‐carbohydrate glycomimetic lectin inhibitors. This work paves the way for a new avenue of research towards innovative anti‐infective drugs. In a more general perspective, such small molecules also hold potential to challenge the hegemony of antibodies for lectin inhibition in clinical use.