Multiple sclerosis (MS) is caused by an autoimmune response against central nervous system (CNS) antigens, resulting in demyelinization of CNS neurons. The matrix metalloproteinase gelatinase B (MMP-9) is produced by T cells and allows transsendothelial migration of activated T cells and antibodies across the blood-brain barrier. Migration of T cells across a basal lamina equivalent in vitro is inhibited by a non-specific MMP inhibitor. Current MS therapies include beta-interferon, which has been shown to reduce the ability of T cells to cross the blood-brain barrier by suppressing MMP-9 production. A specific inhibitor of MMP-9 should therefore have efficacy in prevention or modification of MS attacks without the side effects caused by non-specific activities of current therapies. We propose to use the powerful combinatorial technique of phage display to isolate optimal substrate peptides and high affinity peptides that bind to an inhibit MMP-9. We will construct phage display libraries using information about the structure of MMP-o and its substrates, and will screen these libraries to identify ligands with the desired binding and inhibitory characteristics. In future experiments, the molecules that are isolated will be tested in an established primate model of MS, and then will be developed for clinical evaluation in patients.
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