Research published in Nature Chemical Biology reveals that three specific inhibitors of a cell death pathway, termed necroptosis, all target and inhibit RIP1 kinase, a protein that can direct cells into necrosis. Induced by trauma such as a heart attack or stroke, this form of necrotic death can result in tissue damage contributing to death or long-term disability. The findings present a novel avenue for drug development.
“Our research found that RIP1 kinase can be inhibited by three small molecules: necrostatin-1, -3 and -5,” reports first author Alexei Degterev, PhD, assistant professor at Tufts University School of Medicine and member of the biochemistry program faculty of the Sackler School of Graduate Biomedical Sciences. “Overall, these data establish RIP1 kinase as a new target for therapeutic drug development for human diseases involving necrotic tissue injury, and they establish necrostatins as first-in-class potent and selective inhibitors of RIP1 kinase,” the authors write, including last author, Junying Yuan, PhD, professor at Harvard Medical School.
Necrosis is relevant to many diseases, particularly those that involve an acute event, such as heart attack or stroke. “Cells are programmed to die when they reach the end of their lifecycle and that regulated process is called apoptosis. Cells can also be killed through pathways not controlled by apoptosis. Until recently, this type of cell death, termed necrosis, was believed to be unregulated, a type of accidental cell death caused when cells are placed under extreme stress such as during a heart attack, stroke or organ failure,” says Degterev.
Previous research, as well as research by others, determined that necroptosis, one type of necrosis, is regulated (like apoptosis) and has a specific biochemical pathway. “Through our previous work, we have developed potent and specific small molecules capable of preventing necroptosis in isolated cells,” explains Degterev. This work, done in Yuan’s lab at Harvard, was subsequently awarded patents. “The next step, then, was to look for the target of the inhibition by necrostatins to understand how they inhibit necroptosis. We were particularly interested in RIP1 kinase because it was previously reported by other groups to be important for necroptosis and necrostatin-1 looked similar to known kinase inhibitors.”
The researchers employed several molecular techniques to determine the role these necrostatins played in inhibiting necroptosis. To test whether necrostatin-1 is a RIP1 kinase inhibitor in vitro, researchers added necrostatin-1 in incremental doses to purified RIPI kinase, and observed a dose-dependent decrease in its activity (phosphorylation). To validate their discovery, the researchers made small and specific structural changes to necrostatin-1, to see if loss of the RIP1 kinase inhibition resulted in the inability of the necrostatin-1 analogs to prevent necrosis. Similar experiments were conducted for necrostatin-3 and necrostatin-5 with similar results, which was surprising as the structure of these two molecules are very different from necrostatin-1. Further, based on the results of their analysis, researchers put forward the model describing mechanisms of RIP1 inhibition by necrostatin-1.
“Next, research needs to determine the cellular pathway initiated by RIP1 kinase activity, develop better tools to further investigate its role in human disease, and establish how necrostatins are able to prevent RIP1 kinase from signaling the cell to kill itself,” says Degterev. “This may one day result in effective therapies, currently not available, for many life-threatening diseases.”
“These findings on RIP1 kinase inhibitors suggest entirely new possibilities to investigating the role of necroptosis in disease and indicate that these inhibitors may provide ways to prevent extensive tissue damage,” says Naomi Rosenberg, PhD, dean at the Sackler School of Graduate Biomedical Sciences and vice dean for research at Tufts University School of Medicine. “Discoveries like this reveal how basic science research provides the foundation to our understanding of disease and can point toward possible novel therapeutic strategies to ease the burden of those diseases.”
This work was supported in part by grants to Harvard from the National Institute of General Medicines (NIGMS), the National Institute on Aging (NIA), and the National Institute of Neurological Disorders and Stroke (NINDS), and by funding from the Harvard Center for Neurodegeneration and Repair. Alexei Degterev is a recipient of a NIA Mentored Research Scientist Career Development Award and a Massachusetts Medical Foundation Smith Family New Investigator Award. NIGM, NIA, NINDS are institutes of the National Institutes of Health.
Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Nature Chemical Biology. 2008 (May);Vol 4, Issue 5. “Identification of RIP1 kinase as a specific cellular target of necrostatins.” Published online: April 13 2008, doi 10.1038/nchembio.83
About Tufts University School of Medicine
Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. The Sackler School undertakes research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.
Siobhan E. Gallagher | EurekAlert!
Could this protein protect people against coronary artery disease?
17.11.2017 | University of North Carolina Health Care
Microbial resident enables beetles to feed on a leafy diet
17.11.2017 | Max-Planck-Institut für chemische Ökologie
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,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
17.11.2017 | Physics and Astronomy
17.11.2017 | Health and Medicine
17.11.2017 | Studies and Analyses