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Title: Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling

Abstract

Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC{sub 50} of 0.9 {micro}M and a K{sub i} of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.

Authors:
; ; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
DEFENSE THREAT REDUCTION AGENCY (DTRA)
OSTI Identifier:
1049235
Report Number(s):
BNL-96916-2012-JA
Journal ID: ISSN 0907-4449; 400403709; TRN: US201217%%570
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Acta Crystallographica D: Biological Crystallography
Additional Journal Information:
Journal Volume: D68; Journal Issue: Pt 5; Journal ID: ISSN 0907-4449
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CLOSTRIDIUM BOTULINUM; CRYSTAL STRUCTURE; DESIGN; DISEASES; PEPTIDES; PROTEINS; SIMULATION; STRUCTURE-ACTIVITY RELATIONSHIPS

Citation Formats

Kumar, G, Swaminathan, S, Kumaran, D, and Ahmed, S A. Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling. United States: N. p., 2012. Web. doi:10.1107/S0907444912003551.
Kumar, G, Swaminathan, S, Kumaran, D, & Ahmed, S A. Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling. United States. doi:10.1107/S0907444912003551.
Kumar, G, Swaminathan, S, Kumaran, D, and Ahmed, S A. Tue . "Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling". United States. doi:10.1107/S0907444912003551.
@article{osti_1049235,
title = {Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure-activity relationship and pharmacophore modeling},
author = {Kumar, G and Swaminathan, S and Kumaran, D and Ahmed, S A},
abstractNote = {Clostridium botulinum neurotoxins are classified as Category A bioterrorism agents by the Centers for Disease Control and Prevention (CDC). The seven serotypes (A-G) of the botulinum neurotoxin, the causative agent of the disease botulism, block neurotransmitter release by specifically cleaving one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins and induce flaccid paralysis. Using a structure-based drug-design approach, a number of peptide inhibitors were designed and their inhibitory activity against botulinum serotype A (BoNT/A) protease was determined. The most potent peptide, RRGF, inhibited BoNT/A protease with an IC{sub 50} of 0.9 {micro}M and a K{sub i} of 358 nM. High-resolution crystal structures of various peptide inhibitors in complex with the BoNT/A protease domain were also determined. Based on the inhibitory activities and the atomic interactions deduced from the cocrystal structures, the structure-activity relationship was analyzed and a pharmacophore model was developed. Unlike the currently available models, this pharmacophore model is based on a number of enzyme-inhibitor peptide cocrystal structures and improved the existing models significantly, incorporating new features.},
doi = {10.1107/S0907444912003551},
journal = {Acta Crystallographica D: Biological Crystallography},
issn = {0907-4449},
number = Pt 5,
volume = D68,
place = {United States},
year = {2012},
month = {5}
}