SYNTHESIS OF SELECTIVE C-TYPE LECTIN ANTAGONIST GLYCOMIMETICS

In this thesis we have tackled the problem of identifying high-affinity, selective CLR ligands with two different approaches: in the first approach, we synthesized a diversity library and screened it in microarray format against a group of human CLRs; in the second approach we proceeded to the computer-aided design of a high affinity ligand for the dendritic cell CLR DC-SIGN. In the first approach, we prepared a mannosylated (based on the structure of Manalpha1-2Man) and fucosylated glycomimetic library that was printed on microarray chips. We optimized and validated the proper presentation of the glycomimetics with plant, fungal and bacterial lectins of known specificity. The glycomimetic chip was then screened against available human CLRs and the results were further assessed in complementary assays, such as SPR. In the second approach we targeted the dendritic cell-specific receptor DC-SIGN, which is responsible for the uptake and dissemination of numerous infectious pathogens, such as HIV-1, Dengue, Ebola, M. tuberculosis, etc. Selective inhibitors of the lectin have high potential as anti-microbial therapeutics, but so far, only a handful of monovalent ligands have reached low micromolar affinities. A virtual fragment screening campaign indicated a novel, exploitable binding pocket near the primary sugar binding site of DC-SIGN. Glycomimetic ligands previously developed in our group were functionalized in the appropriate position to reach this pocket, and modified with various substituents in order to form additional interactions. One of the highest affinity DC-SIGN ligands up-to-date was synthesized and X-ray structure analysis proved the in silico predicted interactions with the amino acid residues around the new binding site.