Spring '23 Department Seminars with Dr. Petra Ménová
Title: Drug-like ligands for DC-SIGN receptor
Speaker: Dr. Petra Ménová
Department of Organic Chemistry, University of Chemistry and Technology
Prague, Czech Republic
Date: March 30, 2023, Thursday
Time: 12:30 TRT, 11:30 CET
Lectins are carbohydrate-binding proteins that play important roles in cell-cell recognition, cell migration and immunitv. Their targeting is challenging because of inherent pronerties of their natural substrates carbohydrates: high polarity, low enzymatic stability, low affinity and ability to bind to numerous targets. While nature overcomes these problems with multivalency and exploits the recognition of oligo and polysaccharides, medicinal chemists glycomimetics – synthetic structures that may or may not contain a carbohydrate-based core and lipophilic fragments that interact with non-polar regions of the protein.
DC-SIGN is a lectin receptor expressed on the surface of dendritic cells and macrophages. It recognized mannose- and fucose-containing carbohvdrates in the alvcocalvx of numerous pathogens and mediates their recognition and elimination. As for other lectins, its carbohydrate binding site is shallow and hydrophilic and does not interact well with drug-like molecules
We employ the principles of fragment-based drug discovery to identify secondary binding sites on DC-SIGN and develop new ligands for this interesting target. Several non-carbohydrate scaffolds have been identified and evaluated in structure-activitv relationship studies. An approach called fraament linking led to several hits with improved binding affinity and allosteric activity. Carbohydrate-based glycomimetics showed interesting properties when interacting with secondary binding sites rather that the carbohydrate binding site.
In my lecture, I will explain the principles of fragment-based drug discovery and show some prominent examples from this field. Then I will introduce DC-SIGN as a target and show the results of fragment screening. I will talk about the synthesis of different classes of glycomimetic DC-SIGN ligands and describe several biophysical methods that are used to evaluate their binding. Finally, I will show several possible applications of the described compounds.
Short Biography of the Speaker:
Dr. Petra Ménová received her B.Sc. in drug synthesis and production and M.Sc. in organic chemistry from the University of Chemistry and Technology, Prague. She obtained her Ph.D. in bioorganic chemistry of nucleic acids jointly at UCT Prague and Czech Academy of Sciences. In 2015 she joined the Peter Seeberger group at the Max Planck Institute of Colloids and Interfaces as Marie Skłodowska-Curie postdoctoral fellow. There, she focused on the synthesis of semi-synthetic carbohydrate vaccines. She established her own research group at UCT Prague in 2017. Her main interests are medicinal chemistry, carbohydrate chemistry and small-molecule lectin ligands. She was awarded the Alfred Bader Prize for Bioorganic Chemistry in 2020 and the Julie Hamáčková Prize for Contribution to Science, Research, Pedagogy and Innovation in 2022.