Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A

John H Cardellina 2nd; Virginia I Roxas-Duncan; Vicki Montgomery; Vanessa Eccard; Yvette Campbell; Xin Hu; Ilja Khavrutskii; Gregory J Tawa; Anders Wallqvist; James B Gloer; Nisarga L Phatak; Ulrich Höller; Ashish G Soman; Biren K Joshi; Sara M Hein; Donald T Wicklow; Leonard A Smith

doi:10.1021/ml200312s

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. eCollection 2012 May 10.

Authors

John H Cardellina 2nd¹, Virginia I Roxas-Duncan¹, Vicki Montgomery¹, Vanessa Eccard¹, Yvette Campbell¹, Xin Hu², Ilja Khavrutskii², Gregory J Tawa², Anders Wallqvist², James B Gloer³, Nisarga L Phatak³, Ulrich Höller³, Ashish G Soman³, Biren K Joshi³, Sara M Hein³, Donald T Wicklow⁴, Leonard A Smith⁵

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.

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.