Biosynthetic Pathway of CMP-Sialic Acid

The synthesis of sialic acid in animals involves a multi-step process: (1) Using uracil diphosphate-N-acetylglucosamine (UDPGlcNAc) as the starting substrate, N-acetyl-D-mannosamine (ManNAc) is generated under the action of glucosamine-6-phosphate N-acetyltransferase/ManNAc kinase (GNE/MNK). (2) The kinase functions of the same enzyme phosphorylate sugar to produce ManNAc-6-P. (3) ManNAc-6-P and phosphoenolpyruvate generate N-acetylneuraminic acid 9-phosphate (Neu5Ac-9-P) under the catalysis of NeuAc-9-P-synthase. (4) The precursor is dephosphorylated by Neu5Ac-9-P-phosphatase to further generate Neu5Ac. (5) Neu5Ac is transferred to the nucleus, where it is catalyzed by CMP-NeuAc synthetase (CMAS) and connected to cytidine 5'-triphosphate (CTP) to produce the donor substrate CMP-Neu5Ac. Activation of CMP-sialic acid (CMP-Neu5Ac or CMP-KDN) is a prerequisite for incorporation into glycoconjugates.

Sialic acid is related to a variety of biological processes, the development of CMP-sialic acid inhibitors will help explore new disease treatment strategies and drug targets.

CMP-Sialic Acid Inhibitor Development Service at CD BioGlyco

• Inhibitor screening service

CD BioGlyco has an advanced high-throughput screening (HTS) technology that uses self-built compound libraries to conduct CMP-sialic acid inhibitor screening service. CMAS activates CMP in the nucleus, producing the active inhibitor, which competitively blocks sialyltransferase (ST), thereby preventing the incorporation of natural sialic acid into assembled glycans. On the other hand, it induces feedback inhibition of de novo sialic acid biosynthesis, which inactivates GNE/MNK due to the accumulation of CMP-sialic acid in cells, thereby inhibiting sialylation.

At present, we have developed a class of C-5-modified fluorinated sialic acid analogs (SiaFAc), which are structurally similar to Neu5Ac. They are powerful glycomimetics that inhibit abnormal sialylation, in which the C-5 carbamate-fluorinated sialic acids have a strong inhibitory effect on sialylation.

• Structural optimization and modification service

Professional technicians at CD BioGlyco provide structural optimization and modification for mature CMP-sialic acid inhibitors to improve the inhibitory potency of the compounds.

• Activity assessment and mechanism studies

CD BioGlyco uses different methods to evaluate the inhibitory activity of candidate inhibitors against CMP-sialic acid and further investigate its mechanism of action. At the same time, we also provide pharmacokinetic evaluation for candidate CMP-sialic acid inhibitors and conduct absorption, distribution, metabolism, excretion, and toxicology experiments on samples to determine the pharmacokinetic properties and safety of candidate inhibitors.

Fig.1 CMP-Sialic acid inhibitor development service. (CD BioGlyco)

Publication

Technology: Flow cytometry

Journal: Molecular Cancer Therapeutics

IF: 6.011

Published: 2013

Results: The authors evaluated the blocking of sialy-glycan synthesis in mouse melanoma B16F10 cells by fluorinated sialic acid analogs and their effects on cell adhesion, migration, and tumor cells in vivo. The results demonstrated that P-3F_ax-Neu5Ac selectively inhibited sialylation in mouse melanoma cells. At the same time, the growth rate of B16F10 cells treated with the inhibitor was significantly delayed in vivo, so the inhibitor reduced the growth of tumor cells.

Fig.2 Blocking sialylation reduced tumor growth in vivo. (Büll, et al., 2013)

Applications

• Antiviral drug research: Many viruses use sialic acid for recognition and binding when infecting host cells. By developing CMP-sialic acid inhibitors, it is possible to interfere with the interaction between viruses and host cells and block the virus invasion and replication process.
• Cancer research: Sialic acid modification on the surface of tumor cells has an important impact on tumor growth, metastasis, and immune evasion. CMP-sialic acid inhibitors, which interfere with the sialic acid modification process of tumor cells, inhibit tumor development and metastasis and provide new targets for tumor treatment.
• Biological research: The development of CMP-sialic acid inhibitors is applied in the field of biological research to explore the functions and mechanism of sialic acid and reveal its importance in cell signaling and pathological processes.

Advantages

• CD BioGlyco has a strong technical team that is familiar with the biological properties of CMP-sialic acid and provides mature CMP-sialic acid inhibitor synthesis and structure optimization services.
• CD BioGlyco provides custom CMP-sialic acid inhibitor development services, including molecular design, synthesis optimization, activity screening, and structure optimization.
• We use various advanced technical means to accelerate the development process of CMP-sialic acid inhibitors and provide acceptable results within the specified time.

CD BioGlyco has a self-built small molecule compound library and a mature Inhibitor Development Service. We provide efficient CMP-sialic acid inhibitor development service. Please feel free to contact us if you are interested in our development details.