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Structure Based Discovery of Pan Active Botulinum Neurotoxin Inhibitors | OMICS International| Abstract
ISSN: 2332-0877

Journal of Infectious Diseases & Therapy
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  • Research Article   
  • J Infect Dis Ther 2017, Vol 6(1): 351
  • DOI: 10.4172/2332-0877.1000351

Structure Based Discovery of Pan Active Botulinum Neurotoxin Inhibitors

Casey Vieni1, Brian McGillick1,2, Desigan Kumaran1, Subramaniam Eswaramoorthy1, Palani Kandavelu3 and Subramanyam Swaminathan1*
1Biology Department, Brookhaven National Laboratory, , Upton, New York 11973, USA
2Biochemistry and Structural Biology Department, Medical Scientist Training Program, Stony Brook University, Stony Brook, New York 11794, USA
3SER-CAT and Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, USA
*Corresponding Author : Subramanyam Swaminathan, Biology Department, Brookhaven National Laboratory, Upton, New York 11973, USA, Email: [email protected]

Received Date: Jan 05, 2018 / Accepted Date: Feb 10, 2018 / Published Date: Feb 14, 2018

Abstract

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 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 h window before botulism can be diagnosed. Using structure-based drug 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.

Keywords: Clostridium botulinum neurotoxins; Structure-based drug discovery; Pan-active; Peptide inhibitors; three-dimensional structure; Foot-print signature

Citation: Vieni C, McGillick B, Kumaran D, Eswaramoorthy E, Kandavelu P, et al. (2018) Structure Based Discovery of Pan Active Botulinum Neurotoxin Inhibitors. J Infect Dis Ther 6: 351. Doi: 10.4172/2332-0877.1000351

Copyright: © 2018 Vieni C, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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