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A peptidomimetic inhibitor of matrix metalloproteinases containing a tetherable linker group

Cao, Yang, Croll, Tristan I., Rizzi, Simone C., Shooter, Gary K., Edwards, Helen E., Finlayson, Kathleen, Upton, Zee, & Dargaville, Tim R. (2011) A peptidomimetic inhibitor of matrix metalloproteinases containing a tetherable linker group. Journal of Biomedical Materials Research Part A, 96A(4), pp. 663-672.

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Abstract

Successful wound repair and normal turnover of the extracellular matrix relies on a balance between matrix metalloproteinases (MMPs) and their natural inhibitors (the TIMPs). When over-expression of MMPs and abnormally high levels of activation or low expression of TIMPs are encountered, excessive degradation of connective tissue and the formation of chronic ulcers can occur. One strategy to rebalance MMPs and TIMPs is to use inhibitors. We have designed a synthetic pseudopeptide inhibitor with an amine linker group based on a known high-affinity peptidomimetic MMP inhibitor have demonstrated inhibition of MMP-1, -2, -3 and -9 activity in standard solutions. The inhibitor was also tethered to a polyethylene glycol hydrogel using a facile reaction between the linker unit on the inhibitor and the hydrogel precursors. After tethering, we observed inhibition of the MMPs although there was an increase in the IC50s which was attributed to poor diffusion of the MMPs into the hydrogels, reduced activity of the tethered inhibitor or incomplete incorporation of the inhibitor into the hydrogels. When the tethered inhibitors were tested against chronic wound fluid we observed significant inhibition in proteolytic activity suggesting our approach may prove useful in rebalancing MMPs within chronic wounds.

Impact and interest:

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8 citations in Web of Science®

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128 since deposited on 21 Jul 2010
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ID Code: 33198
Item Type: Journal Article
Keywords: Matrix metalloproteinase inhibitor, Polyethylene glycol, Hydrogel, Chronic wound fluid, Hydroxamic acid
DOI: 10.1002/jbm.a.33027
ISSN: 1552-4965
Subjects: Australian and New Zealand Standard Research Classification > ENGINEERING (090000) > BIOMEDICAL ENGINEERING (090300) > Biomaterials (090301)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PUBLIC HEALTH AND HEALTH SERVICES (111700) > Aged Health Care (111702)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Past > QUT Faculties & Divisions > Faculty of Science and Technology
Current > Institutes > Institute of Health and Biomedical Innovation
Current > Schools > School of Nursing
Copyright Owner: Copyright 2011 Wiley Periodicals, Inc.
Copyright Statement: The definitive version is available at www3.interscience.wiley.com
Deposited On: 22 Jul 2010 09:55
Last Modified: 05 Sep 2013 15:36

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