Novel Small Molecule Inhibitors of Botulinum Neurotoxin a Metalloprotease Activity

Authors

• James C. Burnett, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• James J. Schmidt, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
• Robert G. Stafford, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA
• Rekha G. Panchal, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• Tam L. Nguyen, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• Ann R. Hermone, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• Jonathan L. Vennerstrom, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA
• Connor F. McGrath, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• Douglas J. Lane, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• Edward A. Sausville, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• Daniel W. Zaharevitz, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• Rick Gussio, Developmental Therapeutics Program, NCI Frederick, Frederick, MD
• Sina Bavari, US Army Medical Research Institute of Infectious Diseases, Frederick, MD 21702, USA

Document Type

Article

Date of this Version

2003

Comments

Published in Biochemical and Biophysical Research Communications 310 (2003) 84–93.

Abstract

Botulinum neurotoxins (BoNTs) are among the most lethal biological substances to have been weaponized and are listed as biodefense category A agents. Currently, no small molecule (non-peptidic) therapeutics exist to counter this threat; hence, identifying and developing compounds that inhibit BoNTs is a high priority. In the present study, a high-throughput assay was used to identify small molecules that inhibit the metalloprotease activity of BoNT serotype A light chain (BoNT/A LC). All inhibitors were further verified using a HPLC-based assay. Conformational analyses of these compounds, in conjunction with molecular docking studies, were used to predict structural features that contribute to inhibitor binding and potency. Based on these results, a common pharmacophore for BoNT/A LC inhibitors is proposed. This is the first study to report small molecules (non-peptidics) that inhibit BoNT/A LC metalloprotease activity in the low lM range.