Submitted to: ACS Medicinal Chemistry Letters
Publication Type: Peer reviewed journal
Publication Acceptance Date: 4/2/2012
Publication Date: 4/2/2012
Citation: Cardellina, J., Roxas-Duncan, V., Montgomery, V., Eccard, V., Campbell, Y., Hu, X., Khavrutskii, I., Tawa, G.J., Wallqvist, A., Gloer, J.B., Phatak, N.L., Hoeller, U., Soman, A., Joshi, B.K., Hein, S.M., Wicklow, D.T., Smith, L.A. 2012. Fungal bis-naphthopyrones as inhibitors of botulinum neurotoxin serotype A. ACS Medicinal Chemistry Letters. 3(5):387-391. Interpretive Summary: Botulinum neurotoxins (BoNT’s), produced by the bacterium Clostridium botulinum are the causative agents of botulism, a neuroparalytic illness. Food borne or inhalational intoxications can result in sustained paralysis that necessitates long term supportive care consisting of intubation and ventilation. BoNTs are also popularly used for cosmetic purposes, and as therapies for a range of medical conditions. Intentional and/or accidental misuse of the toxins has brought about the urgent needs for effective therapeutics of botulism. The research describes the fungal metabolites “bis-naphthopyrones” as a novel class of BoNT inhibitors deserving further investigation. These are the first fungal natural products reported to inhibit botulinum neurotoxin serotype A.
Technical Abstract: An in silico screen of the Molecular Library Small Molecule Repository (MLSMR) of ˜350,000 compounds and confirmatory bioassays led to identification of the fungal natural product chaetochromin A (1) as an inhibitor of botulinum neurotoxin serotype A (BoNT A). Subsequent acquisition and testing of analogs of 1 uncovered two analogs with improved activity, talaroderxines A (2) and B (3). These are the first fungal metabolites reported to exhibit BoNT/A inhibitory activity.