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In diseases such as Crohn's and rheumatoid arthritis, the immune system mistakenly attacks the body's tissues. But now scientists have managed to trick the immune systems of mice into targeting one of the body's players in autoimmune processes, an enzyme known as MMP9. The results of their research appear today in Nature Medicine.
Prof. Irit Sagi of the Biological Regulation Department and her research group have spent years looking for ways to home in on and block members of the matrix metalloproteinase (MMP) enzyme family.
These proteins cut through support materials in our bodies such as collagen, crucial for cellular mobilization, proliferation and wound healing, and more. But when some proteins, especially MMP9, get out of control, they aid and abet autoimmune disease and cancer metastasis. Blocking these proteins might lead to effective treatments for a number of diseases.
Originally, Sagi and others had designed synthetic drug molecules targeting MMPs. But these drugs had extremely severe side effects. Normal MMP inhibitors, known as TIMPs, keep enzymes in line using an arm on each TIMP precisely constructed to fit into a cleft in an enzyme sheltering the active MMP a metal zinc ion surrounded by three histidine peptides closing it off like a snug cork.
"Unfortunately," says Sagi, "it is quite difficult to reproduce this precision synthetically."
Dr. Netta Sela-Passwell began working on an alternative approach. She and Sagi decided to try and trick the immune system to create natural antibodies targeting MMP-9 through immunization. Immunization uses a killed virus to induce the immune system to create antibodies that attack live viruses; perhaps an MMP immunization would trick the body into creating antibodies to block the enzyme at its active site.
Together with Prof. Abraham Shanzer, they created an artificial version of the metal zinc-histidine complex at the heart of the MMP9 active site.
They injected these small, synthetic molecules into mice and afterward checked the mice's blood for signs of immune activity against the MMPs. They called antibodies they found 'metallobodies.' These were similar but not identical to TIMPS.
A detailed analysis of the 'metallobodies' atomic structure suggested they work in a similar way reaching into the enzyme's cleft and blocking the active site. The metallobodies were selective for just two members of the MMP family MMP2 and 9 and bound tightly to both mouse and human versions of these enzymes.
As hoped, when they had induced an inflammatory condition mimicing Crohn's disease in mice, the symptoms were prevented when mice were treated with metallobodies.
"We are excited not only by the potential of this method to treat Crohn's," says Sagi, "but by the potential of using this approach to explore novel treatments for many other diseases."
Yeda, the technology transfer arm of the Weizmann Institute has applied for a patent for the synthetic immunization molecules as well as the generated metallobodies.
Also participating in this research were Drs. Orly Dym, Haim Rozenberg, Raanan Margalit, Rina Arad-Yellin and Tsipi Shoham of the Structural Biology, Immunology and Biological Regulation Departments, Raghavendra Kikkeri of the Organic Chemistry Department, Miriam Eisenstein of the Chemical Research Support Department, Ori Brenner of the Veterinary Resources Department and Tamar Danon of the Molecular Cell Biology Department.
Prof. Irit Sagi's research is supported by the Spencer Charitable Fund; the Leona M. and Harry B. Helmsley Charitable Trust; Cynthia Adelson, Canada; Mireille Steinberg, Canada; the Leonard and Carol Berall Post Doctoral Fellowship; and the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research. Prof. Sagi is the incumbent of the Maurizio Pontecorvo Professorial Chair.
The Weizmann Institute of Science in Rehovot, Israel, is one of the world's top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,700 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.
Weizmann Institute news releases are posted on the World Wide Web at http://wis-wander.weizmann.ac.il/, and are also available at http://www.eurekalert.org/
Original article: http://wis-wander.weizmann.ac.il/new-synthetic-molecules-treat-autoimmune-disease-in-mice