a target for the drug

The MMP9 enzyme facilitates the spread of metastases, at the Weizmann Institute they found a way to inhibit it

When cancer metastases spread in the body, or when acute inflammation occurs, it can be assumed that these processes involve enzymes from the matrix metalloproteinases family, or, for short, MMP. These enzymes cut different materials, including tough collagen fibers that strengthen and connect the body's tissues. One member of this family, the enzyme MMP9, is often produced in cancer cells that break away from their original tumor, and embark on a wandering journey through the bloodstream on their way to establishing a new cancer metastasis. Tissues attacked by the immune system, when an autoimmune disease occurs in the body, also produce this enzyme. In short, this is an enzyme whose appearance portends bad news. Therefore, many scientists, in different parts of the world, are looking for a way to block its activity in an attempt to develop a treatment for these diseases.

The required first step in the quest to block MMP9 is deciphering the three-dimensional spatial structure of its molecule. Although, various parts of the enzyme structure have been previously deciphered, including the active segment, but since the active segments of all MMP enzymes are similar to each other, there is no point in designing drugs to inhibit them. Medicines aimed at inhibiting the active segment of one enzyme will also inhibit all the other "family members", which may cause strong and negative side effects. Therefore attention was directed to the flexible part in the center of the enzyme (called the connector domain). But unfortunately, this part of the molecule is particularly difficult to image with the usual methods.

Prof. Irit Sagi and the members of the research group she heads, in the Department of Structural Biology in the Faculty of Chemistry at the Weizmann Institute of Science, decided to face this challenge. They used an unconventional combination of techniques to reveal the complete molecular structure of MMP9. The members of the team, besides Prof. Sagi, included research student Gabriel Rosenblum from the Department of Structural Biology at the Weizmann Institute, Dr. Rotem Serchuk from the Biological Services Unit, research student Philip van den Steen and Prof. Gislein Opdenacker from the University of Leuven, Belgium, and with his assistance
of Dr. Sidney Cohen from the Department of Chemical Research Infrastructures at the Weizmann Institute of Science, used a variety of methods, each of which was based on the information found in the previous method. The methods included chemical tests, structural deciphering through X-ray scattering analysis ("X-ray"), imaging of a single enzyme in measurements with an atomic force microscope - and sophisticated data processing that enabled connection between the various methods. In this way, the scientists were able to discover the structure of the enzyme molecule, which includes the connector domain. It turns out that this molecular space is characterized by great flexibility, which is unique only to MMP9 and does not exist in other members of this family. These findings were published in the scientific journal Structure.

It is possible that the unique and flexible binding domain of MMP9 will ultimately be its Achilles heel: the scientists, led by Prof. Sagi, have already succeeded in designing a molecule that binds to this domain and neutralizes its activities. The Yedah company, which promotes industrial applications based on the inventions of Weizmann Institute of Science scientists, has already submitted an application for a patent on the molecule, which may form the basis of a new drug to curb cancer metastases and autoimmune diseases.