For more than 20 years, scientists have been developing drugs that block a family of matrix metalloproteinases (MMPs) in order to treat a variety of diseases ranging from cancer to inflammatory diseases. But clinical trials on a variety of promising small molecules have failed because these drugs lack the specificity needed to target faulty MMPs while still allowing “good” MMPs to perform their regular cellular duties.
Clinical trial failures indicate that selective, rather than broad-based, MMP inhibitors are required for successful MMP therapies. However, achieving this selectivity with small-molecule inhibitors is difficult. As a result, broad-spectrum small molecule inhibitors have failed in clinical trials due to their low efficacy and deleterious side effects.
Prof. Min Xue and his colleague at the University of California, Riverside have developed peptide-based selective MMP-2 inhibitors with nanomolar activities. Unlike known MMP inhibitors, n-TIMP-2 and GM6001 that inhibit a broad spectrum of the MMP family, these peptide inhibitors do not exhibit off-target effects with other MMP family members such as MMP-9.
Fig. 1 shows how a proMMP2 inhibitor (orange) interferes with the protein-protein interaction (PPI) between proMMP2 and TIMP2 (tissue inhibitor of metalloproteinases 2). This PPI inhibition blocks the TIMP2-assisted proMMP2 activation process and thereby results in lower levels of active MMP2.
Fig. 2 shows the novel UCR MMP-2 peptide binds to proMMP2 with an Kd of 2.3 nM and inhibits MMP2 activation with an IC50 of 20 nM.