CD BioGlyco is a biological company specializing in research services in the field of glycobiology. We have a comprehensive Glycosylation Inhibitor Development process to meet the needs of our clients in O-GlcNAc, N-Glycosylation, O-Glycosylation, etc. O-GlcNAc glycosylation modification, as a unique glycosylation modification on the nucleus and cytoplasmic proteins, is closely related to several physiological processes, such as cellular transcription and protein translation. The development of O-GlcNAc inhibitors helps to advance the study of the biological functions of O-GlcNAc glycosylation modification. We provide multidirectional O-GlcNAc inhibitor development services.
The O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) cycles regulate O-GlcNAc glycosylation modification. Hexosamine biosynthetic pathway (HBP) provides the substrate for this process. We focus on developing inhibitors for key enzymes involved in O-GlcNAc glycosylation.
Fig.1 Directions for the development of O-GlcNAc inhibitors. (CD BioGlyco)
OGA is the only enzyme that removes O-GlcNAc from target proteins. UDP-GlcNAc is the substrate sugar donor for this highly dynamic and reversible modification process. Most of the currently developed OGA inhibitors are analogs or transition-state analogs of UDP-GlcNAc. These inhibitors are competitive inhibitors of OGA that competitively bind the key site of the enzyme with the substrate. Based on the reported types of OGA inhibitors, we screen, design, and synthesize compounds that inhibit OGA enzyme activity.
OGT catalyzes the addition of N-acetylglucosamine from UDP-GICNAc to specific Ser or Thr residues of target proteins to form β-O-glycosidic linkages. Based on the published reports, we develop OGT inhibitors in three main directions: UDP backbone inhibitors, dual-substrate inhibitors, and small-molecule inhibitors for high-throughput screening (HTS).
Structural analogs with the substrate UDP-GICNAc (OGT substrate donor) and UDP (O-GICNAc reaction product) are potential inhibitors of OGT.
Dual-substrate analogs based on donor substrates and acceptor substrates may balance high binding affinity with high selectivity.
We use fluorescent luminescent HTS methods to rapidly and efficiently obtain small molecule inhibitors with novel backbones and new binding mechanisms. HTS-based small molecule inhibitors are diverse in type and structure. Most of them act on the C-terminal catalytic pocket of OGT and have a single mode of action.
To better meet our clients' needs for inhibitor development, we further divide the direction of OGT inhibitor development.
The glutamine biosynthesis pathway is the main pathway of glucose metabolism. UDP-GlcNAc is synthesized through this pathway and is used to regulate the glycosylation modification of O-GICNAc. GFAT is the rate-limiting enzyme. We construct a GFAT inhibitor screening method. Our goal is to screen compounds with high selectivity and inhibitory activity.
Fig.2 Process of O-GlcNAc inhibitor development. (CD BioGlyco)
Technology: Drug design, molecular docking
Journal: European Journal of Medicinal Chemistry
IF:6.7
Published: 2022
Results: In this study, the OGA inhibitor Thiamet-G was modified and adapted according to its binding mode with OGA. A novel inhibitor scaffold containing three parts was finally designed and synthesized. The compounds containing the new scaffold were then studied and screened. And the in vivo and in vitro inhibitory effects of these compounds on OGA were tested. Finally, a non-glycosylated OGA inhibitor was successfully screened. This compound has the potential to be a therapeutic agent for Alzheimer's disease. This study also provides a new inspiration for the development of OGA inhibitors.
Fig.3 The rationales for the design of non-sugar OGA inhibitors. (Li, et al., 2022)
CD BioGlyco aims to develop glycosylation inhibitors with high potency and selectivity. Based on our highly qualified personnel and well-established development process, we are confident to provide the best service. Feel free to contact us to tell us about your needs. Our client service staff will be the first to answer your questions.
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