Characterization and Carbohydrate Specificity of Pradimicin S
| Autor: | Yasuhiro Igarashi, Carole A. Bewley, Jan Balzarini, Rodolfo Ghirlando, Syed Shahzad-ul-Hussan, Cajetan Dogo-Isonagie |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Anti-HIV Agents
Stereochemistry viruses Mannose HIV Infections Pradimicin S HIV Envelope Protein gp120 Biochemistry Article Catalysis Mannans chemistry.chemical_compound Colloid and Surface Chemistry Sulfation Anti-Infective Agents Mannobiose Humans Anthracyclines Trisaccharide chemistry.chemical_classification virus diseases General Chemistry Nuclear magnetic resonance spectroscopy Virus Internalization Carbohydrate Small molecule humanities chemistry HIV-1 Calcium Trisaccharides |
| Zdroj: | Journal of the American Chemical Society. 134:12346-12349 |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | The pradimicin family of antibiotics is attracting attention due to its anti-infective properties and as a model for understanding the requirements for carbohydrate recognition by small molecules. Members of the pradimicin family are unique among natural products in their ability to bind sugars in a Ca(2+)-dependent manner, but the oligomerization to insoluble aggregates that occurs upon Ca(2+) binding has prevented detailed characterization of their carbohydrate specificity and biologically relevant form. Here we take advantage of the water solubility of pradimicin S (PRM-S), a sulfated glucose-containing analogue of pradimicin A (PRM-A), to show by NMR spectroscopy and analytical ultracentrifugation that at biologically relevant concentrations, PRM-S binds Ca(2+) to form a tetrameric species that selectively binds and engulfs the trisaccharide Manα1-3(Manα1-6)Man over mannose or mannobiose. In functional HIV-1 entry assays, IC(50) values of 2-4 μM for PRM-S corrrelate with the concentrations at which oligomerization occurs as well as the affinities with which PRM-S binds the HIV surface envelope glycoprotein gp120. Together these data reveal the biologically active form of PRM-S, provide an explanation for previous speculations that PRM-A may contain a second mannose binding site, and expand our understanding of the characteristics that can engender a small molecule with the ability to function as a carbohydrate receptor. |
| Databáze: | OpenAIRE |
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