Often, simply identifying the structure of a potential drug target protein and designing a molecule to block it are not enough. Just ask Prof. Irit Sagi, a chemist turned biology researcher, who recently developed a clever technique for directing the body to design its own protein-blocking molecules.
Sagi studies an enzyme called matrix metalloproteinase 9 (MMP-9). This protein, along with other members of the MMP family, cleaves straight through the support tissues in the body – collagen and the extracellular matrix that gives organs and tissues structure. This, of course is crucial for everything from wound healing to cell mobility but when dysregulated, MMP-9 in particular often finds its skills subverted to cancer metastasis and autoimmune syndromes. Sagi knows this protein inside out – she has investigated its active site, used innovative structural methods she developed in her lab to observe the dynamic conformations it goes through when activated, and identified weak points in the structure. Blocking the protein was not the main challenge. The problem lay in creating a selective molecule that would only block MMP-9 and not its many sister enzymes, all of which have a similar, metal-ion-based setup in their active sites. At least one small molecule blocker for this enzyme even made it to clinical trials, but the side effects were severe: Apparently it obstructed the activity of too many other MMP enzymes.
The idea for an alternative approach arose when Dr. Netta Sela-Passwell was an M.Sc. student on Sagi’s lab. Instead of directly attacking the enzyme, the scientists looked for a way to trick the body’s own regulatory system into stepping up activity. The plan was to design a synthetic molecule that would trigger an immune response against the metal-ion-based set up at the enzyme’s active site.
In mice, the synthetic molecules Sagi and her lab team eventually created in collaboration with an organic chemistry group – pared-down versions of the enzyme’s active site – performed as hoped: They significantly reduced symptoms of a Crohn’s-like autoimmune disease. Interestingly enough, when the researchers checked the mice’s blood, they found antibodies that were similar, but not identical to, inhibitors that the body normally produces to regulate the harmful activity of MMP-9. Testing these near-natural mouse antibodies on human versions of the enzyme revealed the same binding and blocking activity, and they only bound to one other member of the MMP family, rather than all of them.
Of course, the path from a method that works in mice to one that can be packaged as a drug for humans is long and treacherous. But Sagi and her team are excited by their finding – not just for its potential to treat a debilitating condition, but because it presents a whole new approach to dealing with human enzymes that are involved in promoting and abetting disease.