SYNTHESIS OF INHIBITORS OF BOTULINUM METALLOPROTEASES

Information

  • Research Project
  • 2024568
  • ApplicationId
    2024568
  • Core Project Number
    R41GM056025
  • Full Project Number
    1R41GM056025-01
  • Serial Number
    56025
  • FOA Number
  • Sub Project Id
  • Project Start Date
    6/1/1997 - 27 years ago
  • Project End Date
    5/30/1998 - 26 years ago
  • Program Officer Name
  • Budget Start Date
    6/1/1997 - 27 years ago
  • Budget End Date
    5/30/1998 - 26 years ago
  • Fiscal Year
    1997
  • Support Year
    1
  • Suffix
  • Award Notice Date
    5/12/1997 - 27 years ago
Organizations

SYNTHESIS OF INHIBITORS OF BOTULINUM METALLOPROTEASES

DESCRIPTION: (Adapted from the applicant's abstract) This proposal describes strategies to synthesize potent non-competitive inhibitors of botulinum neurotoxin metalloproteases {BoNT protease}. These metalloproteases which are the molecular effectors of the paralytic effects of these toxins are the most selective proteases reported due to allosteric activation of the enzyme by a portion of the substrate. Conformationally-restricted analogs of known substrate "activation" sequences will be synthesized to develop peptide- derived inhibitors that inhibit at a non-competitive site on the enzyme. Yeast two-hybrid experiments will be used to identify the enzyme residues at the activation site. When the bioactive conformation has been elucidated, it will become possible to develop non-peptide templates for creating novel inhibitors of these proteases. During Phase I, the applicants will synthesize a set of conformationally restricted compounds and determine their inhibitory activity using the established assay. Known substrates are cleaved by the toxin metalloprotease to generate fragments with an electrophoretic mobility different from those of the uncleaved substrates. These compounds are expected to function as pharmacological antagonists and to serve as important probes useful for neurobiological research as adjuncts for reversing effects of BoNT in treating achalasia and related disorders in humans and as important lead compounds in antitoxin drug development.

IC Name
NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
  • Activity
    R41
  • Administering IC
    GM
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
  • Sub Project Total Cost
  • ARRA Funded
  • CFDA Code
    821
  • Ed Inst. Type
  • Funding ICs
  • Funding Mechanism
  • Study Section
    ZRG3
  • Study Section Name
  • Organization Name
    PROMEGA CORPORATION
  • Organization Department
  • Organization DUNS
  • Organization City
    MADISON
  • Organization State
    WI
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    537115399
  • Organization District
    UNITED STATES