Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A

  • ACS Med Chem Lett. 2012 Apr 2;3(5):387-91. doi: 10.1021/ml200312s.
John H Cardellina 2nd  1 ,  Virginia I Roxas-Duncan  1 ,  Vicki Montgomery  1 ,  Vanessa Eccard  1 ,  Yvette Campbell  1 ,  Xin Hu  2 ,  Ilja Khavrutskii  2 ,  Gregory J Tawa  2 ,  Anders Wallqvist  2 ,  James B Gloer  3 ,  Nisarga L Phatak  3 ,  Ulrich Höller  3 ,  Ashish G Soman  3 ,  Biren K Joshi  3 ,  Sara M Hein  3 ,  Donald T Wicklow  4 ,  Leonard A Smith  5
Affiliations
  • 1. Division of Integrated Toxicology, U.S. Army Medical Research Institute of Infectious Diseases , Frederick, Maryland 21702-5011.
  • 2. Biotechnology High Performance Computer Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command , Frederick, Maryland 21702.
  • 3. Department of Chemistry, University of Iowa , Iowa City, Iowa 52242-1294.
  • 4. Bacterial Foodborne Pathogens and Mycology Research Unit, Agricultural Research Service, U.S. Department of Agriculture , Peoria, Illinois 61604.
  • 5. Senior Research Scientist for Medical Countermeasures Technology, U.S. Army Medical Research Institute of Infectious Diseases , Frederick, Maryland 21702-5011.
PMID: 24900483 DOI: 10.1021/ml200312s
Abstract

An in silico screen of the NIH Molecular Library Small Molecule Repository (MLSMR) of ∼350000 compounds and confirmatory bioassays led to identification of chaetochromin A (1) as an inhibitor of botulinum neurotoxin serotype A (BoNT A). Subsequent acquisition and testing of analogues of 1 uncovered two compounds, talaroderxines A (2) and B (3), with improved activity. These are the first Fungal metabolites reported to exhibit BoNT/A inhibitory activity.

Keywords
binding free energy; botulinum neurotoxin serotype A; chaetochromin; in silico screen; natural products; talaroderxine; thermodynamic integration.
Products