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Pharmacophore Refinement Guides the Design of Nanomolar-Range Botulinum Neurotoxin Serotype A Light Chain Inhibitors

  1. Author:
    Nuss, J. E.
    Dong, Y. X.
    Wanner, L. M.
    Ruthel, G.
    Wipf, P.
    Gussio, R.
    Vennerstrom, J. L.
    Bavari, S.
    Burnett, J. C.

  2. Author Address

    [Nuss, Jonathan E.; Wanner, Laura M.; Ruthel, Gordon; Bavari, Sina] USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. [Dong, Yuxiang; Vennerstrom, Jonathan L.] Univ Nebraska Med Ctr, Coll Pharm, Dept Pharmaceut Sci, Omaha, NE 68198 USA. [Wipf, Peter] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. [Wipf, Peter] Univ Pittsburgh, Combinatorial Chem Ctr, Pittsburgh, PA 15260 USA. [Gussio, Rick] Natl Canc Inst Frederick, Dev Therapeut Program, Frederick, MD 21702 USA. [Burnett, James C.] Natl Canc Inst Frederick, Target Struct Based Drug Discovery Grp, SAIC Frederick Inc, Frederick, MD 21702 USA.;Bavari, S, USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA.;sina.bavari@us.army.mil burnettjames@mail.nih.gov
    1. Year: 2010
    2. Date: Oct
  2. Journal: Acs Medicinal Chemistry Letters
    1. 1
    2. 7
    3. Pages: 301-305
  4. Type of Article: Article
  5. ISSN: 1948-5875
  1. Abstract:

    Botulinum neurotoxins (BoNTs) are the deadliest of microbial toxins. The enzyme's 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 regionisomers [K-i = 0.600 mu M (+/-0.100 mu M)], with a novel lead bis-[3-amide-5-(imidazolino) phenyl]terephthalamide (BAIPT)-based SMNPI [K-i = 8.52 mu M (+/-0.53 mu M)], resulted in a refined four zone pharmacophore. The refined model guided the design of BAIPT-based SMNPIs possessing K-i values = 0.572 (+/-0.041 mu M) and 0.900 mu M (0.078 mu M).

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External Sources

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  2. DOI: 10.1021/ml100056v
  3. View record in Web of Science®
  4. WOS: 000283100900001

Library Notes

  1. Fiscal Year: FY2010-2011
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