Oligosaccharide Derivative-based Sialylation Inhibitor Development at CD BioGlyco

Sialylated oligosaccharides play a crucial role in almost all routine functions involving multiple cells. It has been found that the expression of sialylation oligosaccharides is upregulated in the development of several types of cancer. At CD BioGlyco, we offer custom sialylation inhibitor development services.

• Receptor-based inhibitors
  • We will develop selective inhibitors based on receptor type. The classification is based on the branched/straight chain structure of the oligosaccharide derivatives, the electronic effect and spatial resistance of the special functional groups, etc. We have developed different types of inhibitors by modifying different positions of the oligosaccharides.
  • Immediately thereafter, we will test the binding of the resulting inhibitors to the donor. One promising example is the introduction of fluorine atoms into the mucin core 2-branched oligosaccharides, which selectively provide a high degree of inhibitory activity.
• Donor-based inhibitors
  We will rationally design and optimize inhibitors that mimic natural donor inhibitors based on the core part of the donor. The main modification in this regard is the sialic acid part. We utilize several derivatives with different substituents to replace the sialic acid portion to obtain oligosaccharide derivatives. The designed inhibitor binds to the active site of sialyltransferase and prevents the transfer of sialic acid by competing with the donor, thus providing a good inhibition effect.

Fig.1 Oligosaccharide derivative-based sialylation inhibitor development. (CD BioGlyco)

Publication

Technology: Designing effective sialyltransferase (ST) inhibitors for oligosaccharide modification

Journal: Biomedicine & Pharmacotherapy

IF: 7.5

Published: 2023

Results: The authors used a ligand-based drug design strategy to develop ST inhibitors based on the natural donor cytidine 5'-monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac). The designed inhibitors bind to the active site of ST and prevent sialic acid transfer by competing with the natural donor CMP-Neu5Ac. In general, modification of sugar fragments yields promising active compounds. The group's extensive work has shown that transition state mimics based on S_N2-like mechanisms are potent ST inhibitors, specifically targeting ST6 galactose-I. It is hypothesized that the transition state occurs via an oxocarbazone ion-like structure on a twisted half-chair conformational ring. In one of their first successful attempts to model this transition, sialic acid was partially replaced by 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en). Two important modifications were rationally introduced. First, a double bond was introduced between C2-C3 to make the isocaprocarbons and oxocarbonium intermediate identically planar. Second, the extended distance between the isohead carbon and the phosphate group of the CMP was mimicked, leaving an extra carbon.

Fig.2 Timeline of donor-based ST inhibitors. (Saoud, et al., 2023)

Applications

• Oligosaccharide derivative-based sialylation inhibitors can be used to probe cellular and molecular recognition, e.g. cell-matrix interactions, receptor binding, etc.
• Oligosaccharide derivative-based sialylation inhibitors can be used in studies of anti-tumor as well as anti-cancer agents.
• Oligosaccharide derivative-based sialylation inhibitors can be used to study the function of oligosaccharides in organisms.

Advantages

• Our inhibitor development services are expected to advance the research process of physiological activities.
• Our glycosylation inhibitor R&D team develops custom development solutions for each client.
• Our technology supports the development of glycosylation inhibitors for various types of oligosaccharide derivatives.

CD BioGlyco is knowledgeable in the Development of Glycosylation Inhibitors. Our researchers have comprehensive and specialized knowledge of glycobiology to help our clients solve their inhibitor development challenges. If you are interested in our services, please feel free to contact us.