You are cordially invited to attend the seminar organized by the Department of Chemistry.
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 (Bilkent time), 11:30 CET
This is an online seminar. To request the event link, please send a message to department.
Abstract:
Lectins are carbohydrate-binding proteins that play important roles in
cell-cell recognition, cell migration and immunitv. Their targeting is
challenging because of inherent properties 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-activity 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.