The biosynthesis of mannose-rich glycoconjugates requires the conversion of monosaccharides into activated sugar nucleotides, which requires multiple enzyme catalysis, such as GDP-mannose pyrophosphorylase (GDP-MP), phosphomannomutase (PMM), dolichol phosphate-mannose synthase (DPMS), and phosphomannose isomerase (PMI). The sequential action of PMM and GDP-MP converts mannose-6-phosphate (M-6-P) into GDP-mannose. GDP-Mannose is an important glycosylation substrate and plays a vital role in the glycosylation process. By developing GDP-Mannose inhibitors, we interfere with glycosylation reactions, regulating cell surface glycosylation modifications, thereby affecting a variety of biological processes and related diseases.
CD BioGlyco has established diverse Glycosylation Inhibitor Development solutions and provides professional GDP-mannose inhibitor development services. The service contents are as follows:
GDP-MP is an important enzyme in the biosynthesis of mannose-containing complex sugars, which is applied as a target for the development of new inhibitors. CD BioGlyco has a self-built small molecule chemical library. We have developed a highly sensitive, multi-well plate-based enzyme activity assay method that uses phosphate detection technology to conduct HTS of the small molecule chemical library to identify GDP-MP inhibitors and screen potential inhibitor candidates.
CD BioGlyco re-confirms the screened compounds through GDP-MP assay and counter-screening assay technology to avoid false positive results. After identifying the GDP-MP inhibitors, we perform a dose-response assay to quantify the compound's IC50 and thereby determine its inhibitory potency.
CD BioGlyco evaluates the inhibitory activity of compounds based on the inhibitory potency of each GDP-MP inhibitor using appropriate biological and biochemical experimental techniques, including in vitro and in vivo cell experiments.
CD BioGlyco uses structure-activity relationship analysis and medicinal chemistry methods to optimize and modify the structure of existing GDP-mannose inhibitors to improve their activity, selectivity, and pharmacokinetic properties. We have developed some GDP-MP inhibitors, such as 4-pyrazin-4-ylquinolines, 2-substituted quinolines, alkyl-resorcinol derivatives, etc.
Fig.1 GDP-Mannose inhibitor development service. (CD BioGlyco)
Journal: Antimicrobial Agents and Chemotherapy
Results: Since Leishmania synthesizes mannose-rich glycoconjugates, the authors used HTS technology to develop new anti-Leishmania compounds based on the principle that GDP-MP inhibitors inhibit GDP-mannose production. Twenty compounds were obtained through HTS, and the anti-Leishmania activity of the obtained compounds was evaluated in promastigote-infected macrophages. The results indicated that compound 3 had an obvious inhibitory effect, which belonged to the 4-pyrazin-4-ylquinoline class and was selectively toxic to Leishmania amastigotes.
Fig.2 Treatment of Leishmania major-infected mouse macrophages with GDP-MP inhibitors. (Lackovic, et al., 2010)
CD BioGlyco is a leading biotechnology company in the world. We closely follow the development of science and technology, master the latest research progress and technological applications, and carry out the GDP-mannose inhibitors development in an efficient and precise manner. Please feel free to contact us if you would like to inquire about detailed development services.