Researchers Found New Artificial Molecules’ Role In Treatment Of Autoimmune Disease In Mice

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Our body has always been capable of protecting itself from infectious microorganism, through the immune system. However, there are times when the immune system betrays the human body, by acting against it. This precipitates the onset of so-called autoimmune diseases like rheumatoid arthritis and Crohn’s disease. A variety of studies had been conducted to develop new therapies against these diseases. The scientists from the Weizmann Institute were able to trick the mice’s immune systems to attack the MMP9, an enzyme attributed to be among the body’s players in autoimmune mechanisms. The findings can be found in Nature Medicine, December 26th issue.

Prof. Irit Sagi from the Biological Regulation Department and her colleagues have invested time to determine means to halt the members of the matrix metalloproteinase (MMP) enzyme family. These proteins can penetrate the body’s support materials like collagen, making them important in mobilizing cells, proliferation and wound healing. However, when MMP9, a member of this enzyme family, becomes uncontrollable, they can assist in autoimmune diseases processes and cancer metastasis. Additionally, obstructing these enzymes may result to development of effective therapies for various diseases.

Sagi and her team have originally crafted synthetic drug molecules which can directly fight MMPs; nonetheless, these drugs were evaluated to be just rudimentary and had hazardous side effects. TIMPs (MMP inhibitors) are normally produced by the body to strictly regulate this enzyme’s activity. Moreover, these work in a strictly selective mechanism, compared with the synthetic drugs. They would accurately create an arm on every TIMP to reach into a cleft in the MMP enzyme that encloses the active part (three histidine peptides around a metal zinc ion), closing it like a snug stopper.  However, this was not materialized because its accuracy is hard to synthetically reproduce.

Dr. Netta Sela-Passwell and Sagi opted to try to trick the immune system in order to make natural antibodies which can attack MMP-9 through immunization, instead of designing a synthetic molecule that can directly target MMPs. An MMP immunization would provoke the body to produce antibodies which can obstruct the enzyme at its active site. This was compared with the effect of immunization with a killed virus, which can cue the immune system to produce antibodies that can combat the viruses.

They made a synthetic form of the metal zinc-histidine complex at the heart of the MMP9 active site, with the aid of Prof. Abraham Shanzer from the Organic Chemistry Department. These small, artificial molecules were injected into the mice; then, they observed the mice’s blood for any sign of immune response against the MMPs. They discovered the ‘metallobodies” that were the same but not identical with TIMPS. They made a thorough analysis of their atomic structure. The metallobodies were selective for MMP2 and 9, two members of the MMP enzyme family; they tightly bonded with both the human and the mouse versions of the enzymes.

Furthermore, upon the induction of a Crohn’s disease-alike inflammatory condition in mice and they were treated with metallobodies, the signs had not been manifested. Sagi expressed their excitement about this new approach and the possibility of utilizing it in developing new therapies for other diseases. Moreover, a patent for the synthetic immunization molecules and the metallobodies has been applied for by the technology transfer arm of Weizmann Institute—Yeda.




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