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 trick the immune system to create natural antibodies that target 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, 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/
Yivsam Azgad | idw
New catalyst controls activation of a carbon-hydrogen bond
21.11.2017 | Emory Health Sciences
The main switch
21.11.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
The WHO reports an estimated 429,000 malaria deaths each year. The disease mostly affects tropical and subtropical regions and in particular the African continent. The Fraunhofer Institute for Silicate Research ISC teamed up with the Fraunhofer Institute for Molecular Biology and Applied Ecology IME and the Institute of Tropical Medicine at the University of Tübingen for a new test method to detect malaria parasites in blood. The idea of the research project “NanoFRET” is to develop a highly sensitive and reliable rapid diagnostic test so that patient treatment can begin as early as possible.
Malaria is caused by parasites transmitted by mosquito bite. The most dangerous form of malaria is malaria tropica. Left untreated, it is fatal in most cases....
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
21.11.2017 | Physics and Astronomy
21.11.2017 | Physics and Astronomy
21.11.2017 | Life Sciences