VSE knjižnice (vzajemna bibliografsko-kataložna baza podatkov COBIB.SI)
  • Design, synthesis and evaluation of novel inhibitors and proteolysis-targeting chimeras for human galectin-8 [Elektronski vir] = Načrtovanje, sinteza in vrednotenje novih zaviralcev in himernih razgrajevalcev človeškega galektina-8 : doktorska disertacija
    Purić, Edvin
    Galectin-8 plays an important role in innate and adaptive immune responses, as it is involved in a wide variety of physiological processes and in a number of diseases, making it an interesting target ... for highly potent and selective galectin-8N inhibitors. In our work, we have designed compound libraries, starting from a known galectin-8N inhibitor, which has a low micromolar affinity for galectin-8N and slight selectivity towards galectin-3, which has a similar binding site to galectin-8N. Our strategy led to the first inhibitors of galectin-8N with Kd values in the nanomolar inhibition range and slightly improved selectivity towards galectin-3, compared to the lead compound. Isothermal titration calorimetry (ITC) revealed important differences in enthalpic and entropic contributions to the binding and indicated a very interesting thermodynamic footprint of the selected galectin-8N inhibitors. We solved a crystal structure of the 2-O-propargyl derivative in complex with the N-terminal domain of galectin-8, showing a close contact between the acetylene moiety of the co-crystallised ligand and the guanidine moiety of the Arg45 side chain. Further quantum mechanical calculations confirmed a new type of interaction, which has not been previously identified and can be characterized as a non-canonical cation-π interaction. Besides, we proved that the fluorescence polarization assay is a reliable screening method and can be used for high-throughput screening of galectin-8N inhibitors. A new fluorescent probe was designed, which requires fewer synthesis steps compared to a tetrasaccharide LNnT probe and can be alternatively used in screening of galectin-8N inhibitors. Together with partners from the University of Florence, we have successfully designed the BODIPY probe and demonstrated its usefulness in studying lectins in fluorescence-based assays. Finally, we were the first to design, synthesize and biologically evaluate chimeric degrader (PROTAC) for galectin-8, which induced galectin-3 and -8 degradation in breast cancer cells. Conversely, none of the designed PROTACs were able to affect galectin-3 and -8 levels in HUVEC cells. The results of the in vitro angiogenesis assay showed changes in tube formation, while the complete inhibition of angiogenesis has not been achieved.
    Vrsta gradiva - disertacija ; neleposlovje za odrasle
    Založništvo in izdelava - Ljubljana : [E. Purić], 2025
    Jezik - angleški
    COBISS.SI-ID - 252007171

    Povezava(-e):

    https://repozitorij.uni-lj.si/IzpisGradiva.php?id=174389

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