The Parkinson's Disease Drug Tolcapone and Analogues are Potent Glycomimetic Lectin Inhibitors of Pseudomonas aeruginosa LecA
Issued Date
2025-01-01
Resource Type
ISSN
14337851
eISSN
15213773
Scopus ID
2-s2.0-105020701772
Journal Title
Angewandte Chemie International Edition
Rights Holder(s)
SCOPUS
Bibliographic Citation
Angewandte Chemie International Edition (2025)
Suggested Citation
Leusmann S., Siebs E., Kuhaudomlarp S., Varrot A., Imberty A., Kuhn B., Lerner C., Grether U., Titz A. The Parkinson's Disease Drug Tolcapone and Analogues are Potent Glycomimetic Lectin Inhibitors of Pseudomonas aeruginosa LecA. Angewandte Chemie International Edition (2025). doi:10.1002/anie.202508864 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/113119
Title
The Parkinson's Disease Drug Tolcapone and Analogues are Potent Glycomimetic Lectin Inhibitors of Pseudomonas aeruginosa LecA
Corresponding Author(s)
Other Contributor(s)
Abstract
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.