The O-glycans synthesis begins with the transfer of N-acetylgalactosamine (GalNAc) from UDP-N-acetylgalactosamine (UDP-GalNAc) to Ser or Thr residues of the glycoprotein, yielding the Tn antigen. The entire process is catalyzed by a multigene family of enzymes called polypeptide N-acetyl-α-galactosaminyltransferases (ppGalNAcTs). The ppGalNAcTs family participates in the progression of many cancers and be used as tumor diagnostic and prognostic markers. At the same time, the development of inhibitors of this enzyme is used as potential targets for anti-cancer immunotherapy.
CD BioGlyco provides various types of O-GalNAc inhibitor development services and conducts synthesis and structural optimization of the screened inhibitors to improve the selectivity and affinity of the inhibitors.
CD BioGlyco has performed a kinetic analysis of ppGalNAcT for the development of peptide inhibitors, observing that endogenous peptide O-GalNAc transferase inhibitor (EPO-G) inhibits ppGalNAc and helping to determine its enzymatic mechanism of action. Another method to inhibit ppGalNAc and thereby inhibit overall O-glycosylation is to use UDP-GalNAc derivatives.
In addition, CD BioGlyco provides high-throughput screening for ppGalNAcT inhibitors based on uridine libraries. The library retains the uridine portion of the nucleotide sugar substrate and uses three different linkers to combine uridine with a variety of bases through oxime or hydrazone bonds. We screen candidate compounds with the potential to inhibit O-GalNAc from the compound library. For example: We have identified ppGalNAcT inhibitors containing 2,3,4-trihydroxyphenyl groups from the library. They inhibit O-glycosylation and induce apoptosis in different cells. We also have screened a class of quinoline compounds T3Inh-1, which is a direct inhibitor of ppGalNAc-T3.
CD BioGlyco uses cell models or in vitro experimental systems to provide O-GalNAc inhibitor activity assessment service, including experiments to determine inhibitor activity and effects on O-GalNAc modification.
Fig.1 O-GalNAc inhibitor development service. (CD BioGlyco)
Technology: High-throughput screening, Flow cytometry
Journal: Chemistry & Biology
Results: The authors screened ppGalNAcT inhibitors that initiate O-linked glycosylation. They used novel high-throughput technology to screen two mppGalNAcT-1 inhibitors 1-68A and 2-68A from a uridine-based library, which inhibited ppGalNAcT 1 -5, 7, 10, and 11, were broad-spectrum inhibitors of the ppGalNAcT family. At the same time, these compounds destroyed O-linked glycosylation in cells and induced apoptosis of human T-cell lymphoma cells.
Fig.2 Screened ppGalNAcT inhibitors. (Hang, et al., 2004)
CD BioGlyco has extensive experience in drug research and enzyme inhibitor development, especially the development of inhibitors for O-GalNAc transferase. We provide a full range of O-GalNAc inhibitor development support and solutions based on client needs. Please feel free to contact us if you're interested in the details of our development.