Featured Research

from universities, journals, and other organizations

New synthetic molecules treat autoimmune disease in mice

Date:
December 30, 2011
Source:
Weizmann Institute of Science
Summary:
A team of scientists has turned the tables on an autoimmune disease. In such diseases, including Crohn's and rheumatoid arthritis, the immune system mistakenly attacks the body's tissues. But the scientists managed to trick the immune systems of mice into targeting one of the body's players in autoimmune processes, an enzyme known as MMP9.

Left: Natural control mechanism blocks the enzyme's zinc active site. Right: Novel antibody works as effectively as the natural control mechanism.
Credit: Image courtesy of Weizmann Institute of Science

A team of Weizmann Institute scientists has turned the tables on an autoimmune disease. In such diseases, including Crohn's and rheumatoid arthritis, the immune system mistakenly attacks the body's tissues. But the scientists 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 recently appeared in Nature Medicine.

Related Articles


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 such support materials in our bodies as collagen, which makes them crucial for cellular mobilization, proliferation and wound healing, among other things. But when some members of the family, especially MMP9, get out of control, they can 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 to directly target MMPs. But these drugs proved to be fairly crude tools that had extremely severe side effects. The body normally produces its own MMP inhibitors, known as TIMPs, as part of the tight regulation program that keeps these enzymes in line. As opposed to the synthetic drugs, these work in a highly selective manner. An arm on each TIMP is precisely constructed to reach into a cleft in the enzyme that shelters the active bit -- 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 as an M.Sc. student in Sagi's lab, and continued on through her Ph.D. research. She and Sagi decided that, rather than attempting to design a synthetic molecule to directly attack MMPs, they would try coaxing the immune system into targeting MMP-9 through immunization. Just as immunization with a killed virus induces the immune system to create antibodies that then attack live viruses, an MMP immunization would trick the body into creating antibodies that block the enzyme at its active site.

Together with Prof. Abraham Shanzer of the Organic Chemistry Department, they created an artificial version of the metal zinc-histidine complex at the heart of the MMP9 active site. They then injected these small, synthetic molecules into mice and afterward checked the mice's blood for signs of immune activity against the MMPs. The antibodies they found, which they dubbed "metallobodies," were similar but not identical to TIMPS, and a detailed analysis of their 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 they bound tightly to both the mouse versions of these enzymes and the human ones.

As they hoped, when they had induced an inflammatory condition that mimics 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, Rina Arad-Yellin and Tsipi Shoham, and Raanan Margalit 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. This work was financially supported by Merck Serono S.A., a division of Merck KGaA, Darmstadt, Germany.


Story Source:

The above story is based on materials provided by Weizmann Institute of Science. Note: Materials may be edited for content and length.


Journal Reference:

  1. Netta Sela-Passwell, Raghavendra Kikkeri, Orly Dym, Haim Rozenberg, Raanan Margalit, Rina Arad-Yellin, Miriam Eisenstein, Ori Brenner, Tsipi Shoham, Tamar Danon, Abraham Shanzer, Irit Sagi. Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential. Nature Medicine, 2011; DOI: 10.1038/nm.2582

Cite This Page:

Weizmann Institute of Science. "New synthetic molecules treat autoimmune disease in mice." ScienceDaily. ScienceDaily, 30 December 2011. <www.sciencedaily.com/releases/2011/12/111225144320.htm>.
Weizmann Institute of Science. (2011, December 30). New synthetic molecules treat autoimmune disease in mice. ScienceDaily. Retrieved December 21, 2014 from www.sciencedaily.com/releases/2011/12/111225144320.htm
Weizmann Institute of Science. "New synthetic molecules treat autoimmune disease in mice." ScienceDaily. www.sciencedaily.com/releases/2011/12/111225144320.htm (accessed December 21, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Sunday, December 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

The Best Tips to Curb Holiday Carbs

The Best Tips to Curb Holiday Carbs

Buzz60 (Dec. 19, 2014) It's hard to resist those delicious but fattening carbs we all crave during the winter months, but there are some ways to stay satisfied without consuming the extra calories. Vanessa Freeman (@VanessaFreeTV) has the details. Video provided by Buzz60
Powered by NewsLook.com
Sierra Leone Bikers Spread the Message to Fight Ebola

Sierra Leone Bikers Spread the Message to Fight Ebola

AFP (Dec. 19, 2014) More than 100 motorcyclists hit the road to spread awareness messages about Ebola. Nearly 7,000 people have now died from the virus, almost all of them in west Africa, according to the World Health Organization. Video provided by AFP
Powered by NewsLook.com
Researchers Test Colombian Village With High Alzheimer's Rates

Researchers Test Colombian Village With High Alzheimer's Rates

AFP (Dec. 19, 2014) In Yarumal, a village in N. Colombia, Alzheimer's has ravaged a disproportionately large number of families. A genetic "curse" that may pave the way for research on how to treat the disease that claims a new victim every four seconds. Duration: 02:42 Video provided by AFP
Powered by NewsLook.com
The Best Protein-Filled Foods to Energize You for the New Year

The Best Protein-Filled Foods to Energize You for the New Year

Buzz60 (Dec. 19, 2014) The new year is coming and nothing will energize you more for 2015 than protein-filled foods. Fitness and nutrition expert John Basedow (@JohnBasedow) gives his favorite high protein foods that will help you build muscle, lose fat and have endless energy. Video provided by Buzz60
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins