skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model

Abstract

Botulinum neurotoxins (BoNTs) are the most poisonous biological substance known to humans. They cause flaccid paralysis by blocking the release of acetylcholine at the neuromuscular junction. Here, we report a number of small molecule non-peptide inhibitors of BoNT serotype E. In addition, the structure–activity relationship and a pharmacophore model are presented. Although non-peptidic in nature, these inhibitors mimic key features of the uncleavable substrate peptide Arg-Ile-Met-Glu (RIME) of the SNAP-25 protein. Among the compounds tested, most of the potent inhibitors bear a zinc-chelating moiety connected to a hydrophobic and aromatic moiety through a carboxyl or amide linker. All of them show low micromolar IC50 values.

Authors:
ORCiD logo [1];  [1];  [1]
  1. Brookhaven National Lab. (BNL), Upton, NY (United States). Biology Department
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1336050
Alternate Identifier(s):
OSTI ID: 1398009
Report Number(s):
BNL-112325-2016-JA
Journal ID: ISSN 0968-0896
Grant/Contract Number:  
SC0012704; AC02-98CH10886; DEAC02-98CH10886
Resource Type:
Accepted Manuscript
Journal Name:
Bioorganic and Medicinal Chemistry
Additional Journal Information:
Journal Volume: 24; Journal Issue: 18; Journal ID: ISSN 0968-0896
Publisher:
Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Botulinum neurotoxin; fluorene; inhibitor; structure-activity relationship; pharmacophore

Citation Formats

Kumar, Gyanendra, Agarwal, Rakhi, and Swaminathan, Subramanyam. Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model. United States: N. p., 2016. Web. https://doi.org/10.1016/j.bmc.2016.06.036.
Kumar, Gyanendra, Agarwal, Rakhi, & Swaminathan, Subramanyam. Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model. United States. https://doi.org/10.1016/j.bmc.2016.06.036
Kumar, Gyanendra, Agarwal, Rakhi, and Swaminathan, Subramanyam. Sat . "Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model". United States. https://doi.org/10.1016/j.bmc.2016.06.036. https://www.osti.gov/servlets/purl/1336050.
@article{osti_1336050,
title = {Small molecule non-peptide inhibitors of botulinum neurotoxin serotype E: Structure–activity relationship and a pharmacophore model},
author = {Kumar, Gyanendra and Agarwal, Rakhi and Swaminathan, Subramanyam},
abstractNote = {Botulinum neurotoxins (BoNTs) are the most poisonous biological substance known to humans. They cause flaccid paralysis by blocking the release of acetylcholine at the neuromuscular junction. Here, we report a number of small molecule non-peptide inhibitors of BoNT serotype E. In addition, the structure–activity relationship and a pharmacophore model are presented. Although non-peptidic in nature, these inhibitors mimic key features of the uncleavable substrate peptide Arg-Ile-Met-Glu (RIME) of the SNAP-25 protein. Among the compounds tested, most of the potent inhibitors bear a zinc-chelating moiety connected to a hydrophobic and aromatic moiety through a carboxyl or amide linker. All of them show low micromolar IC50 values.},
doi = {10.1016/j.bmc.2016.06.036},
journal = {Bioorganic and Medicinal Chemistry},
number = 18,
volume = 24,
place = {United States},
year = {2016},
month = {6}
}

Journal Article:

Citation Metrics:
Cited by: 1 work
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Tetanus and Botulinum Neurotoxins Are Zinc Proteases Specific for Components of the Neuroexocytosis Apparatus
journal, March 1994

  • Schiavo, Giampietro; Rossetto, Ornella; Benfenati, Fabio
  • Annals of the New York Academy of Sciences, Vol. 710, Issue 1 Toxins and Ex
  • DOI: 10.1111/j.1749-6632.1994.tb26614.x

Severe botulism after focal injection of botulinum toxin
journal, November 2006


Analyzing a bioterror attack on the food supply: The case of botulinum toxin in milk
journal, June 2005

  • Wein, L. M.; Liu, Y.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 28
  • DOI: 10.1073/pnas.0408526102

Strategies to Design Inhibitors of Clostridium Botulinum Neurotoxins
journal, March 2007


Separation, purification, partial characterization and comparison of the heavy and light chains of botulinum neurotoxin types A, B, and E.
journal, September 1985


Thioredoxin and Its Reductase Are Present on Synaptic Vesicles, and Their Inhibition Prevents the Paralysis Induced by Botulinum Neurotoxins
journal, September 2014


Structure and function of tetanus and botulinum neurotoxins
journal, November 1995


Proteolysis of SNAP-25 by types E and A botulinal neurotoxins.
journal, January 1994


Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin.
journal, December 1993


Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin
journal, October 1992

  • Schiavo, Giampietro G.; Benfenati, Fabio; Poulain, Bernard
  • Nature, Vol. 359, Issue 6398
  • DOI: 10.1038/359832a0

Identification of the nerve terminal targets of botulinum neurotoxin serotypes A, D, and E.
journal, November 1993


Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synaptobrevin
journal, June 1993


A high-affinity competitive inhibitor of type A botulinum neurotoxin protease activity
journal, December 2002


Catalytic Features of the Botulinum Neurotoxin A Light Chain Revealed by High Resolution Structure of an Inhibitory Peptide Complex
journal, May 2008

  • Silvaggi, Nicholas R.; Wilson, David; Tzipori, Saul
  • Biochemistry, Vol. 47, Issue 21
  • DOI: 10.1021/bi8001067

A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype A Has a Very Different Conformation than SNAP-25 Substrate
journal, October 2008


Structure- and Substrate-based Inhibitor Design for Clostridium botulinum Neurotoxin Serotype A
journal, July 2008

  • Kumaran, Desigan; Rawat, Richa; Ludivico, Matthew L.
  • Journal of Biological Chemistry, Vol. 283, Issue 27
  • DOI: 10.1074/jbc.M801240200

Basic Tetrapeptides as Potent Intracellular Inhibitors of Type A Botulinum Neurotoxin Protease Activity
journal, January 2011

  • Hale, Martha; Oyler, George; Swaminathan, Subramanyam
  • Journal of Biological Chemistry, Vol. 286, Issue 3
  • DOI: 10.1074/jbc.M110.146464

Peptide inhibitors of botulinum neurotoxin serotype A: design, inhibition, cocrystal structures, structure–activity relationship and pharmacophore modeling
journal, April 2012

  • Kumar, Gyanendra; Kumaran, Desigan; Ahmed, S. Ashraf
  • Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 5
  • DOI: 10.1107/S0907444912003551

Identification of a Potent Botulinum Neurotoxin A Protease Inhibitor Using in Situ Lead Identification Chemistry
journal, April 2006

  • Boldt, Grant E.; Kennedy, Jack P.; Janda, Kim D.
  • Organic Letters, Vol. 8, Issue 8
  • DOI: 10.1021/ol0603211

Structures of Clostridium botulinum Neurotoxin Serotype A Light Chain Complexed with Small-Molecule Inhibitors Highlight Active-Site Flexibility
journal, May 2007


Botulinum neurotoxin serotype A inhibitors: Small-molecule mercaptoacetamide analogs
journal, April 2009

  • Moe, Scott T.; Thompson, Andrew B.; Smith, Genessa M.
  • Bioorganic & Medicinal Chemistry, Vol. 17, Issue 8
  • DOI: 10.1016/j.bmc.2009.03.013

An in vitro and in vivo disconnect uncovered through high-throughput identification of botulinum neurotoxin A antagonists
journal, February 2007

  • Eubanks, L. M.; Hixon, M. S.; Jin, W.
  • Proceedings of the National Academy of Sciences, Vol. 104, Issue 8
  • DOI: 10.1073/pnas.0611213104

Synthesis and Biological Evaluation of Botulinum Neurotoxin A Protease Inhibitors
journal, February 2010

  • Li, Bing; Pai, Ramdas; Cardinale, Steven C.
  • Journal of Medicinal Chemistry, Vol. 53, Issue 5
  • DOI: 10.1021/jm901852f

Targeting Botulinum A Cellular Toxicity: A Prodrug Approach
journal, October 2013

  • Šilhár, Peter; Eubanks, Lisa M.; Seki, Hajime
  • Journal of Medicinal Chemistry, Vol. 56, Issue 20
  • DOI: 10.1021/jm400873n

Identification of Clinically Viable Quinolinol Inhibitors of Botulinum Neurotoxin A Light Chain
journal, January 2014

  • Caglič, Dejan; Krutein, Michelle C.; Bompiani, Kristin M.
  • Journal of Medicinal Chemistry, Vol. 57, Issue 3
  • DOI: 10.1021/jm4012164

Structural Framework for Covalent Inhibition of Clostridium botulinum Neurotoxin A by Targeting Cys165
journal, September 2012

  • Stura, Enrico A.; Le Roux, Laura; Guitot, Karine
  • Journal of Biological Chemistry, Vol. 287, Issue 40
  • DOI: 10.1074/jbc.M112.396697

Development of Potent Inhibitors of Botulinum Neurotoxin Type B
journal, September 2003

  • Anne, Christine; Turcaud, Serge; Quancard, Jean
  • Journal of Medicinal Chemistry, Vol. 46, Issue 22
  • DOI: 10.1021/jm0300680

Thio-derived disulfides as potent inhibitors of botulinum neurotoxin type B: implications for zinc interaction
journal, October 2003


Domain Organization in Clostridium botulinum Neurotoxin Type E Is Unique: Its Implication in Faster Translocation
journal, February 2009

  • Kumaran, Desigan; Eswaramoorthy, Subramaniam; Furey, William
  • Journal of Molecular Biology, Vol. 386, Issue 1
  • DOI: 10.1016/j.jmb.2008.12.027

Novel Chimeras of Botulinum Neurotoxins A and E Unveil Contributions from the Binding, Translocation, and Protease Domains to Their Functional Characteristics
journal, April 2008

  • Wang, Jiafu; Meng, Jianghui; Lawrence, Gary W.
  • Journal of Biological Chemistry, Vol. 283, Issue 25
  • DOI: 10.1074/jbc.M710442200

SNAP-25 Substrate Peptide (Residues 180–183) Binds to but Bypasses Cleavage by Catalytically Active Clostridium botulinum Neurotoxin E
journal, September 2008

  • Agarwal, Rakhi; Swaminathan, Subramanyam
  • Journal of Biological Chemistry, Vol. 283, Issue 38
  • DOI: 10.1074/jbc.M803756200

Discovery of a fluorene class of compounds as inhibitors of botulinum neurotoxin serotype E by virtual screening
journal, January 2012

  • Kumar, Gyanendra; Agarwal, Rakhi; Swaminathan, Subramanyam
  • Chemical Communications, Vol. 48, Issue 18
  • DOI: 10.1039/c2cc17158a

Electrostatic effects in proteins: comparison of dielectric and charge models
journal, January 1991

  • Mehler, E. L.; Solmajer, T.
  • "Protein Engineering, Design and Selection", Vol. 4, Issue 8
  • DOI: 10.1093/protein/4.8.903

    Works referencing / citing this record: