Characterization and carbohydrate specificity of pradimicin S

J Am Chem Soc. 2012 Aug 1;134(30):12346-9. doi: 10.1021/ja303860m. Epub 2012 Jul 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracyclines / metabolism
  • Anthracyclines / pharmacology*
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology*
  • Anti-Infective Agents / metabolism
  • Anti-Infective Agents / pharmacology
  • Calcium / metabolism*
  • HIV Envelope Protein gp120 / metabolism*
  • HIV Infections / drug therapy
  • HIV-1 / drug effects*
  • HIV-1 / metabolism
  • Humans
  • Mannans / metabolism
  • Mannose / metabolism
  • Trisaccharides / chemistry
  • Trisaccharides / metabolism*
  • Virus Internalization / drug effects

Substances

  • Anthracyclines
  • Anti-HIV Agents
  • Anti-Infective Agents
  • HIV Envelope Protein gp120
  • Mannans
  • Trisaccharides
  • pradimicin S
  • mannobiose
  • Mannose
  • Calcium