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.
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.
Professional technicians at CD BioGlyco provide structural optimization and modification for mature CMP-sialic acid inhibitors to improve the inhibitory potency of the compounds.
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)
Technology: Flow cytometry
Journal: Molecular Cancer Therapeutics
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-3Fax-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)
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.