Pharmacophore refinement guides the design of nanomolar-range botulinum neurotoxin serotype a light chain inhibitors

Jonathan E. Nuss, Yuxiang Dong, Laura M. Wanner, Gordon Ruthel, Peter Wipf, Rick Gussio, Jonathan L Vennerstrom, Sina Bavari, James C. Burnett

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Botulinum neurotoxins (BoNTs) are the deadliest of microbial toxins. The enzymes' zinc(II) metalloprotease, referred to as the light chain (LC) component, inhibits acetylcholine release into neuromuscular junctions, resulting in the disease botulism. Currently, no therapies counter BoNT poisoning postneuronal intoxication; however, it is hypothesized that small molecules may be used to inhibit BoNT LC activity in the neuronal cytosol. Herein, we describe the pharmacophore-based design and chemical synthesis of potent [non-zinc(II) chelating] small molecule (nonpeptidic) inhibitors (SMNPIs) of the BoNT serotype A LC (the most toxic of the BoNT serotype LCs). Specifically, the three-dimensional superimpositions of 2-[4-(4-amidinephenoxy) phenyl]indole-6-amidine-based SMNPI regioisomers [Ki = 0.600 μM (±0.100 μM)], with a novel lead bis-[3-amide-5-(imidazolino)phenyl] terephthalamide (BAIPT)-based SMNPI [Ki = 8.52 μM (±0.53 μM)], resulted in a refined four-zone pharmacophore. The refined model guided the design of BAIPT-based SMNPIs possessing Ki values = 0.572 (±0.041 μM) and 0.900 μM (±0.078 μM).

Original languageEnglish (US)
Pages (from-to)301-305
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume1
Issue number7
DOIs
StatePublished - Oct 14 2010

Fingerprint

Neurotoxins
Chelation
Light
Molecules
Amides
Amidines
Botulism
Neuromuscular Junction
Poisons
Metalloproteases
Cytosol
Poisoning
Acetylcholine
Zinc
Serogroup
Enzymes

Keywords

  • Botulinum neurotoxin
  • biothreat agent
  • gas-phase pharmacophore
  • rational design
  • small molecule inhibitor

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Pharmacophore refinement guides the design of nanomolar-range botulinum neurotoxin serotype a light chain inhibitors. / Nuss, Jonathan E.; Dong, Yuxiang; Wanner, Laura M.; Ruthel, Gordon; Wipf, Peter; Gussio, Rick; Vennerstrom, Jonathan L; Bavari, Sina; Burnett, James C.

In: ACS Medicinal Chemistry Letters, Vol. 1, No. 7, 14.10.2010, p. 301-305.

Research output: Contribution to journalArticle

Nuss, Jonathan E. ; Dong, Yuxiang ; Wanner, Laura M. ; Ruthel, Gordon ; Wipf, Peter ; Gussio, Rick ; Vennerstrom, Jonathan L ; Bavari, Sina ; Burnett, James C. / Pharmacophore refinement guides the design of nanomolar-range botulinum neurotoxin serotype a light chain inhibitors. In: ACS Medicinal Chemistry Letters. 2010 ; Vol. 1, No. 7. pp. 301-305.
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