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Assessment of Synthetic Matrix Metalloproteinase Inhibitors by Fluorogenic Substrate Assay

Title: Assessment of Synthetic Matrix Metalloproteinase Inhibitors by Fluorogenic Substrate Assay.
Name(s): Lively, Ty J., author
Department of Chemistry and Biochemistry
Type of Resource: text
Genre: Text
Issuance: monographic
Date Issued: 2015
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Matrix metalloproteinases (MMPs) are a family of metzincin enzymes that act as the principle regulators and remodelers of the extracellular matrix (ECM). While MMPs are involved in many normal biological processes, unregulated MMP activity has been linked to many detrimental diseases, including cancer, neurodegenerative diseases, stroke, and cardiovascular disease. To develop tools to investigate MMP functions and potential new therapeutics, matrix metalloproteinase inhibitors (MMPIs) have been designed, synthesized, and tested to regulate MMP activity. Inhibitor potencies were evaluated in terms of half maximal inhibitory concentrations (IC50 point) and apparent inhibition constants (Kiapp) for a series of YHJ cyclopentane and pyrolidine-based mercaptosulfonamide inhibitors using collagenase (MMPs-1), gelatinase A (MMP-2), matrilysin (MMP-7), and gelatinase B (MMP-9). MMPs with a shallow S1' binding pocket (MMP-1 and -7) were unable to distinguish between inhibitors showing low potency for nearly all synthetic analogs, the exception being GM6001. Conversely, potency levels of inhibitors tested with MMPs with an intermediate S1' pocket (MMP-2 and -9) varied among inhibitor. The most interesting variation occurred with YHJ-6-286 which was more than 30-fold more selective for MMP-2 than MMP-9, despite belonging to the same gelatinase class. To investigate the role stereoselectivity plays in enzyme inhibition, a dye-conjugate of inhibitor YHJ-7-52, YHJ-7-207, was tested for MMP-9. Results gathered suggest that the dye component of YHJ-7-207 produces a significant amount of steric hindrance as inhibition assays against MMP-9 revealed YHJ-7-207 having a larger IC50 point and Kiapp value than YHJ-7-52.
Identifier: FSU_migr_uhm-0536 (IID)
Keywords: Matrix metalloproteinases, Matrix metalloproteinase inhibitors, Fluorescence resonance energy transfer, Inhibition constant, Half maximal inhibitory concentration
Submitted Note: A Thesis submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for graduation with Honors in the Major.
Degree Awarded: Spring Semester, 2015.
Date of Defense: April 17, 2015.
Subject(s): Microphysics
Molecular biology
Persistent Link to This Record:
Owner Institution: FSU
Is Part of Series: Honors Theses.

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Lively, T. J. (2015). Assessment of Synthetic Matrix Metalloproteinase Inhibitors by Fluorogenic Substrate Assay. Retrieved from