Matrix Metalloproteinase Activation and Inhibition

O'Connell, James Philip (1995). Matrix Metalloproteinase Activation and Inhibition. PhD thesis The Open University.



Processes leading to the in vitro activation of progelatinase-A, progelatinase-B and procollagenase were examined. Progelatinase-A can be activated by treatment with 4-aminophenyl mercuric acetate or by matrilysin and collagenase. The former induces an intramolecular self-cleavage before further intermolecular cleavages generate the mature enzyme. Whilst matrilysin can process progelatinase-A to the mature form, collagenase can only generate an intermediate by cleaving after N37 in the bait region. This intermediate is identical to that produced by a human tumour cell-line in culture. Gelatinase-A reciprocates the action of collagenase by completing the activation of the latter to generate a form of collagenase with full collagenolytic activity. This has been described as superactivation and is commonly associated with the action of stromelysin. It correlates with the appearance of F81 at the amino-terminus.

The C-terminal domain plays no role in catalysis but may be important for in vivo activity. This is particularly evident for collagenase which loses the ability to cleave collagen in its absence. The interaction between collagenase and collagen was shown to be a potential target for designing inhibitors of collagen breakdown.

The properties of a series of reversible, competitive hydroxamic acid matrix metalloproteinase inhibitors were studied. Incorporation of a phenylpropyi group in the P1' position produced inhibitors with picomolar affinities for the gelatinases and discriminated against collagenase and matrilysin and other classes of zinc metallopeptidases. The high affinity of these inhibitors for gelatinase-A was shown to derive from a combination of diffusion limited association rates and very slow dissociation rates.

Methods were developed to allow the study of the pharmacokinetic properties of these inhibitors. Chemical modifications at the P2’ and P3’ positions were shown to result in inhibitors with oral bioavailabilities of greater than 30% in the mouse.

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