skip to main content

DOE PAGESDOE PAGES

Title: Structure Based Discovery of Pan Active Botulinum Neurotoxin Inhibitors

Clostridium botulinum neurotoxins (BoNTs) released by the bacterium Clostridium botulinum are the most potent toxins causing the fatal disease called botulism. There are seven distinct serotypes of BoNTs (A to G) released by various strains of botulinum. They all have high sequence homology and similar three-dimensional structure. The toxicity of BoNT follows a four-step process – binding, internalization, translocation, and cleavage of its target protein, one of the three components of the SNARE complex (Soluble N-ethylmaleimde-sensitive factor attachment protein receptor) required for membrane docking and neurotransmitter release. Cleavage of one of the three proteins causes blockage of neurotransmitter release leading to flaccid paralysis. Though anyone of the above four steps could be a target for developing antidotes for botulism, the catalytic domain is the most suitable target for post exposure treatment. Of the seven serotypes BoNT/A, B, E and probably F affect humans, with BoNT/A considered to be the most potent. Development of drugs for botulism is focused on serotype specific inhibitors, but a pan-active inhibitor acting on several serotypes is preferable since it is difficult to identify the serotype before the treatment, especially since there is at least a 36-hour window before botulism can be diagnosed. Using structure-based drugmore » discovery, we have developed three heptapeptides based on the SNARE proteins which inhibit BoNT/A, B and E equally well. Probable reasons for pan-activity of these peptides are discussed.« less
Authors:
 [1] ;  [2] ;  [1] ;  [1] ;  [3] ;  [1]
  1. Brookhaven National Lab. (BNL), Upton, NY (United States). Dept. of Biology
  2. Brookhaven National Lab. (BNL), Upton, NY (United States). Dept. of Biology; Stony Brook Univ., NY (United States). Dept. of Biochemistry and Structural Biology, Medical Scientist Training Program
  3. Univ. of Georgia, Athens, GA (United States). SER-CAT and Dept. of Biochemistry and Molecular Biology
Publication Date:
Report Number(s):
BNL-203310-2018-JAAM
Journal ID: ISSN 2332-0877
Grant/Contract Number:
SC0012704; AC02-98CH10886
Type:
Accepted Manuscript
Journal Name:
Structure Based Discovery of Pan Active Botulinum Neurotoxin Inhibitors
Additional Journal Information:
Journal Volume: 6; Journal Issue: 1; Journal ID: ISSN 2332-0877
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); USDOD; Defense Threat Reduction Agency (DTRA)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Clostridium botulinum neurotoxins; Structure-based drug discovery; Pan-active; Peptide inhibitors; three-dimensional structure; Foot-print signature
OSTI Identifier:
1425108