Inhibition of Matrix Metalloproteinases: An examination of the S1′ pocket

Miller, Andrew T.; Askew, Marion; Beckett, R.Paul; Bellamy, Claire L.; Bone, Elisabeth A.; Coates, Rachael E.; Davidson, Alan H.; Drummond, Alan H.; Huxley, Philip; Martin, Fionna M.; Saroglou, Lydia; Thompson, Alison J.; Dijk, Sonja E. van; Whittaker, Mark

doi:10.1016/s0960-894x(96)00602-6

Cited by 27 publications

(16 citation statements)

References 23 publications

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“…The carboxylic acid derivatives are actually the precursors of the hydroxamate inhibitors previously discussed (Chapman et al, ; Miller et al, ). The hydroxamate inhibitors were made because the carboxylic acid derivatives were weak in potency and had low oral bioavailability relative to hydroxamate inhibitors.…”

Section: Matrix Metalloproteinase Inhibitorsmentioning

confidence: 96%

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Mittal

Patel

Debs

et al. 2016

Journal Cellular Physiology

147

115

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Matrix metalloproteinases (MMPs) are a diverse group of proteolytic enzymes and play an important role in the degradation and remodeling of the extracellular matrix (ECM). In normal physiological conditions, MMPs are usually minimally expressed. Despite their low expression, MMPs have been implicated in many cellular processes ranging from embryological development to apoptosis. The activity of MMPs is controlled at three different stages: (1) transcription; (2) zymogen activation; and (3) inhibition of active forms by tissue inhibitor metalloproteinases (TIMPs). They can collectively degrade any component of ECM and basement membrane, and their excessive activity has been linked to numerous pathologies mainly including, but not limited to, tumor invasion and metastasis. The lack of information about several MMPs and the steady stream of new discoveries suggest that there is much more to be studied in this field. In particular, there is a need for controlling their expression in disease states. Various studies over the past 30 years have found that each MMP has a specific mode of activation, action, and inhibition. Drugs specifically targeting individual MMPs could revolutionize the treatment of a great number of health conditions and tremendously reduce their burden. In this review article, we have summarized the recent advances in understanding the role of MMPs in physiological and pathological conditions. J. Cell. Physiol. 231: 2599-2621, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Matrix Metalloproteinase Inhibitorsmentioning

confidence: 96%

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Mittal

Patel

Debs

et al. 2016

Journal Cellular Physiology

147

115

View full text Add to dashboard Cite

show abstract

“…In order to increase hydrophobicity, aiming at a better MMP-2 selectivity, the alkyl chain was elongated with n = 8 to 20 carbon atoms as described in the literature (Levy et al, 1998;Miller et al, 1997;Whittaker et al, 1999). Using galardin ® as template, the activity and selectivity were not really increased with the length of the linear chain.…”

Section: Influence Of the S'1 Subsite: Modulation Of Galardin ® In Gementioning

confidence: 99%

Pharmacomodulation of Broad Spectrum Matrix Metalloproteinase Inhibitors Towards Regulation of Gelatinases

Bourguet¹,

Hornebeck²,

Sápi³

et al. 2012

Enzyme Inhibition and Bioapplications

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“…For this purpose, Miller et al observed the maximum specificity of the inhibitor for MMP-2 in comparison to MMP-1 with addition of a C12 alkyl chain as the P′1 group into the structure of batimastat (IC 50 = 1 and 50000 nM, respectively). Broadhurst et al have described a marimastat analogue containing a C9 linear chain displaying a good MMP-2 inhibitory activity (IC 50 < 0.15 nM) .…”

Section: Introductionmentioning

confidence: 99%

“…Broadhurst et al 29 have described a marimastat analogue containing a C9 linear chain displaying a good MMP-2 inhibitory activity (IC 50 < 0.15 nM). 30 However, Miller et al 28 described the best selectivity for MMP-2 versus MMP-1 with a compound containing a C16 alkyl chain (IC 50 = 0.6 and 5000 nM, respectively). Levy et al 31 modified ilomastat by elongating its alkyl chain to eight carbon atoms.…”

Section: ■ Introductionmentioning

confidence: 99%

Design, Synthesis, and Use of MMP-2 Inhibitor-Conjugated Quantum Dots in Functional Biochemical Assays

et al. 2016

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The development of chemically designed matrix metalloprotease (MMP) inhibitors has advanced the understanding of the roles of MMPs in different diseases. Most MMP probes designed are fluorogenic substrates, often suffering from photo- and chemical instability and providing a fluorescence signal of moderate intensity, which is difficult to detect and analyze when dealing with crude biological samples. Here, an inhibitor that inhibits MMP-2 more selectively than Galardin has been synthesized and used for enzyme labeling and detection of the MMP-2 activity. A complete MMP-2 recognition complex consisting of a biotinylated MMP inhibitor tagged with the streptavidin-quantum dot (QD) conjugate has been prepared. This recognition complex, which is characterized by a narrow fluorescence emission spectrum, long fluorescence lifetime, and negligible photobleaching, has been demonstrated to specifically detect MMP-2 in in vitro sandwich-type biochemical assays with sensitivities orders of magnitude higher than those of the existing gold standards employing organic dyes. The approach developed can be used for specific in vitro visualization and testing of MMP-2 in cells and tissues with sensitivities significantly exceeding those of the best existing fluorogenic techniques.

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Inhibition of Matrix Metalloproteinases: An examination of the S1′ pocket

Cited by 27 publications

References 23 publications

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Intricate Functions of Matrix Metalloproteinases in Physiological and Pathological Conditions

Pharmacomodulation of Broad Spectrum Matrix Metalloproteinase Inhibitors Towards Regulation of Gelatinases

Design, Synthesis, and Use of MMP-2 Inhibitor-Conjugated Quantum Dots in Functional Biochemical Assays

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