A peptidomimetic inhibitor of matrix metalloproteinases containing a tetherable linker group.
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 IC₅₀s 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.
Tissue Repair and Regeneration Program, Queensland University of Technology, Institute of Health and Biomedical Innovation, Kelvin Grove, Queensland 4059, Australia.
Yang
Y
Cao
Tristan I
TI
Croll
Simone C
SC
Rizzi
Gary K
GK
Shooter
Helen
H
Edwards
Kathleen
K
Finlayson
Zee
Z
Upton
Tim R
TR
Dargaville
D004789:Enzyme Activation; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011487:Protein Conformation
D020100:Hydrogels; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D057786:Peptidomimetics; D011092:Polyethylene Glycols