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A peptidomimetic inhibitor of matrix metalloproteinases containing a tetherable linker group
Author(s) -
Cao Yang,
Croll Tristan I.,
Rizzi Simone C.,
Shooter Gary K.,
Edwards Helen,
Finlayson Kathleen,
Upton Zee,
Dargaville Tim R.
Publication year - 2011
Publication title -
journal of biomedical materials research part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.849
H-Index - 150
eISSN - 1552-4965
pISSN - 1549-3296
DOI - 10.1002/jbm.a.33027
Subject(s) - matrix metalloproteinase , linker , extracellular matrix , tissue inhibitor of metalloproteinase , materials science , peptidomimetic , matrix metalloproteinase inhibitor , self healing hydrogels , biophysics , elastin , wound healing , pharmacology , biochemistry , chemistry , biology , medicine , polymer chemistry , immunology , pathology , operating system , peptide , computer science
Successful wound repair and normal turnover of the extracellular matrix relies on a balance between matrix metalloproteinases (MMPs) and their natural tissue inhibitor of metalloproteinases (TIMPs). When overexpression 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 and 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 IC 50 s that 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 partial inhibition in proteolytic activity suggesting this approach may prove useful in rebalancing MMPs within chronic wounds. © 2011 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 2011.