Clavatadine A, a natural product with selective recognition and irreversible inhibition of factor XIa

J Med Chem. 2008 Jun 26;51(12):3583-7. doi: 10.1021/jm800314b.

Abstract

Bioassay-guided fractionation of a CH2Cl2/MeOH extract of the sponge Suberea clavata using the serine protease factor XIa to detect antithrombotic activity led to the isolation of the new marine natural products, clavatadines A and B. Clavatadines A and B inhibited factor XIa with IC50's of 1.3 and 27 microM, respectively. A crystal structure of protein-inhibitor (clavatadine A) complex was obtained and revealed interesting selective binding and irreversible inhibition of factor XIa. The cocrystal structure provides guidance for the design and synthesis of future factor XIa inhibitors as antithrombotic agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Products / chemistry
  • Biological Products / isolation & purification*
  • Chemical Fractionation
  • Crystallography, X-Ray
  • Factor Xa / chemistry
  • Factor Xa Inhibitors*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / isolation & purification*
  • Guanidines / chemistry
  • Guanidines / isolation & purification*
  • Hydrogen Bonding
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Structure
  • Phenylacetates / chemistry
  • Phenylacetates / isolation & purification*
  • Porifera / chemistry*

Substances

  • Biological Products
  • Factor Xa Inhibitors
  • Fibrinolytic Agents
  • Guanidines
  • Phenylacetates
  • clavatadine A
  • Factor Xa