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Developing non-carbohydrate glycomimetics targeted to bacterial lectins

Subject Area Biological and Biomimetic Chemistry
Term from 2017 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 390973730
 
Final Report Year 2024

Final Report Abstract

Competing with sugars for blocking pathogen adhesion. Pathogenic microorganisms (viruses, bacteria, fungi and parasites) have developed strategies that utilizes the sugars present on our tissues for recognition, adhesion and infection process. The protein receptors (lectins) from the pathogens are located on the capsid of viruses, on pili at the surface of bacteria, or are secreted in the form of toxins and virulence factors. Their carbohydrate-binding sites are specific for our sugars. Molecules that could interfere with such lectin/glycan interaction are therefore of high interest as anti-infectious agents. Since they prevent the binding without killing the pathogens, they have different mode of actions than antibiotics and could be of great interest for the arising issues of multiresistant pathogens. A multidisciplinary approach for design of new family of molecules. The challenge is to identify small molecules that would mimics the sugars present on human cells, but would be much simpler to synthetize. The consortium of two French and two German laboratories used a multidisciplinary approach combining virtual and experimental screening of chemical libraries. Millions of compounds were tested by virtual screening for their ability to bind to three receptors from two pathogens of interest, Pseudomonas aeruginosa and Burkholderia cenocepacia. In parallel several libraries of natural compound or of chemically synthetized ones were also tested by experimental approaches. When hits are identified, a whole range of functional assays were performed using nuclear magnetic resonance (NMR) approaches, followed by structure (X-ray, NMR), thermodynamics (ITC) and kinetics (SPR, MD) guided lead optimization. The approach was very successful and we obtained novel compounds able to coordinate the calcium ion often present in bacterial receptors. Discovery of metal-binding pharmacophores (MBP) as a new class of Ca2+-dependent lectin inhibitors creates a foundation for fragmentbased ligand design for future drug discovery campaigns. Our multidisciplinary approach also identified new pockets in the bacterial lectins that could be targeted for designing active inhibitors. For LecA from P. aeruginosa, a druggable pocket is located at the interface between two monomers, and compounds can be designed that bridge between this pocket and the galactose binding site. For BambL from B. ambifaria, a secondary pocket was also identified and showed allosteric effect on the carbohydrate binding one. Finally, new divalent ligands with were developed and applied to catechols. These results have been the object of 13 publications, including 9 with co-authors from France and Germany. The non-carbohydrate inhibitor for LecA as well as the manuscript for the allosteric sites in BambL have both been published in Angewandte Chemie, one of the best journals in chemistry. One international patent has also been deposited.

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