Online citations, reference lists, and bibliographies.

Zinc-binding Groups Modulate Selective Inhibition Of MMPs.

Arpita Agrawal, Diego Romero-Perez, Jennifer A Jacobsen, Francisco Villarreal, Seth M Cohen
Published 2008 · Chemistry, Medicine
Cite This
Download PDF
Analyze on Scholarcy
Share
The need for selective matrix metalloproteinase (MMP) inhibition is of interest because of the range of pathologies mediated by different MMP isoforms. The development of more selective MMP inhibitors (MMPi) may help to overcome some of the undesired side effects that have hindered the clinical success of these compounds. In an effort to devise new approaches to selective inhibitors, herein we describe several novel MMPi and show that their selectivity is dependent on the nature of the zinc-binding group (ZBG). This is in contrast to most current MMPi, which obtain isoform selectivity solely from the peptidomimetic backbone portion of the compound. In the present study, six different hydroxypyrone and hydroxypyridinone ZBGs were appended to a common biphenyl backbone and the inhibition efficiency of each inhibitor was determined in vitro (IC(50) values) against MMP-1, -2, -3, -7, -8, -9, -12, and -13. The results show that the selectivity profile of each inhibitor is different as a result of the various ZBGs. Computational modeling studies were used to explain some trends in the observed selectivity profiles. To assess the importance of the ZBG in a biological model, two of the semiselective, potent MMPi (and one control) were evaluated using an isolated perfused rat heart system. Hearts were subjected to ischemia reperfusion injury, and recovery of contractile function was examined. In this model, only one of the two MMPi showed significant and sustained heart recovery, demonstrating that the choice of ZBG can have a significant effect in a relevant pathophysiological endpoint.



This paper is referenced by
10.1016/j.ejmech.2011.03.033
Synthesis and biological evaluation in U87MG glioma cells of (ethynylthiophene)sulfonamido-based hydroxamates as matrix metalloproteinase inhibitors.
Elisa Nuti (2011)
10.1167/iovs.12-10201
Fibrinogen, riboflavin, and UVA to immobilize a corneal flap--molecular mechanisms.
Stacy L Littlechild (2012)
10.3340/jkns.2016.59.6.551
Metallothinein 1E Enhances Glioma Invasion through Modulation Matrix Metalloproteinases-2 and 9 in U87MG Mouse Brain Tumor Model
Hyuk Hur (2016)
10.2174/0929867325666180326163523
Mechanism and Inhibition of Matrix Metalloproteinases.
Linda Cerofolini (2018)
10.1021/jm101266s
Identifying chelators for metalloprotein inhibitors using a fragment-based approach.
Jennifer A Jacobsen (2011)
10.1186/1471-2105-11-500
Analysis of X-ray Structures of Matrix Metalloproteinases via Chaotic Map Clustering
Ilenia Giangreco (2010)
10.1002/9781119951438.EIBC2694
Developing Ligands to Target Transition Metals in Cancer
Rachel D. Utterback (2019)
Identification of Possible Glyoxalase II Inhibitors as Anticancer Agents by a Customized 3D Structure-Based Pharmacophore Model
Nizar A. Al-Shar’i (2015)
10.1007/s00706-018-2237-4
Mimic catechins to develop selective MMP-2 inhibitors
Antonella Di Pizio (2018)
10.1371/journal.pone.0115859
Screening the Medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum Aminopeptidases, M1, M17 and M18
Alessandro Paiardini (2015)
10.1007/s10822-019-00226-8
Discovery of a nanomolar inhibitor of the human glyoxalase-I enzyme using structure-based poly-pharmacophore modelling and molecular docking
Nizar A. Al-Shar’i (2019)
Biophysical Characterization of the vOTU Proteases from the CCHF and Dugbe Nairoviruses
Glenn C. Capodagli (2014)
10.1097/CRD.0b013e31828c5ced
Vascular extracellular matrix in atherosclerosis.
Dimitry A. Chistiakov (2013)
10.1016/j.bbamcr.2009.08.006
To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition.
Jennifer A Jacobsen (2010)
10.1371/journal.pone.0025597
Insights into the Complex Formed by Matrix Metalloproteinase-2 and Alloxan Inhibitors: Molecular Dynamics Simulations and Free Energy Calculations
Ilenia Giangreco (2011)
10.3390/cells8090984
The Rebirth of Matrix Metalloproteinase Inhibitors: Moving Beyond the Dogma
Gregg B Fields (2019)
10.2174/1381612811319250011
Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT.
Nathalie Matusiak (2013)
10.1097/FJC.0b013e3181a6aa83
Effects of novel semiselective matrix metalloproteinase inhibitors on ex vivo cardiac structure-function.
Diego Romero-Perez (2009)
10.1159/000446703
Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability
Jean Marie Ruddy (2016)
10.1002/ddr.21468
Microbial esterases and ester prodrugs: An unlikely marriage for combating antibiotic resistance.
Erik Matthew Larsen (2019)
10.1007/s00253-017-8414-2
Engineering of the cytochrome P450 monooxygenase system for benzyl maltol hydroxylation
Iori Kozono (2017)
10.3390/s18103249
Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances
Hao Huang (2018)
10.1021/bi401022b
A noncompetitive inhibitor for Mycobacterium tuberculosis's class IIa fructose 1,6-bisphosphate aldolase.
Glenn C. Capodagli (2014)
Diamidodipyrrins as BODIPY dyes and chelator fragment libraries to identify new scaffolds for metalloprotein inhibitors
Jennifer A Jacobsen (2010)
10.1517/14728220802560307
The role of matrix metalloproteinases in the pathophysiology and progression of human nervous system malignancies: a chance for the development of targeted therapeutic approaches?
Ioannis Koutroulis (2008)
10.2165/11318390-000000000-00000
Matrix Metalloproteinase Inhibitors
György Dormán (2012)
10.1517/13543776.2013.779254
New selective inhibitors of MMP-13 for inflammatory diseases: a patent evaluation (W02012151158)
Nian-Guang Li (2013)
10.12816/0038752
Oral Health Status, Salivary MMP-8 and Secretory Leukocyte Peptidase Inhibitor (SLPI) among Uncontrolled Type-I Diabetes Mellitus in Iraqi Patients
Rehab Faisal Ahmed (2017)
Conception de ligands à vocation thérapeutique : combinaison d'approches multidisciplinaires pour comprendre les interactions intermoléculaires
Cécile Rouanet Mehouas (2015)
Design, (radio)synthesis and applications of radiolabelled matrix metalloproteinase inhibitors for PET
Nathalie Matusiak (2015)
10.1016/j.bioorg.2020.103616
Structure-based design and optimization of pyrimidine- and 1,2,4-triazolo[4,3-a]pyrimidine-based matrix metalloproteinase-10/13 inhibitors via Dimroth rearrangement towards targeted polypharmacology.
El Sayed Helmy El Ashry (2020)
10.1111/j.1747-0285.2010.01060.x
From Zn to Mn: The Study of Novel Manganese-binding Groups in the Search for New Drugs against Tuberculosis
Sarah L. Williams (2011)
See more
Semantic Scholar Logo Some data provided by SemanticScholar