Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Stopping unwanted cell death: Implications for drug discovery

15.04.2008
Kinase identified as cellular target for inhibiting necrosis in disease

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!
Further information:
http://www.tufts.edu

Further reports about: Cellular Degterev Harvard Inhibitor Kinase RIP1 necroptosis necrosis necrostatin-1 necrostatins

More articles from Life Sciences:

nachricht New eDNA technology used to quickly assess coral reefs
18.04.2019 | University of Hawaii at Manoa

nachricht New automated biological-sample analysis systems to accelerate disease detection
18.04.2019 | Polytechnique Montréal

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

A stellar flare 10 times more powerful than anything seen on our sun has burst from an ultracool star almost the same size as Jupiter

  • Coolest and smallest star to produce a superflare found
  • Star is a tenth of the radius of our Sun
  • Researchers led by University of Warwick could only see...

Im Focus: Quantum simulation more stable than expected

A localization phenomenon boosts the accuracy of solving quantum many-body problems with quantum computers which are otherwise challenging for conventional computers. This brings such digital quantum simulation within reach on quantum devices available today.

Quantum computers promise to solve certain computational problems exponentially faster than any classical machine. “A particularly promising application is the...

Im Focus: Largest, fastest array of microscopic 'traffic cops' for optical communications

The technology could revolutionize how information travels through data centers and artificial intelligence networks

Engineers at the University of California, Berkeley have built a new photonic switch that can control the direction of light passing through optical fibers...

Im Focus: A long-distance relationship in femtoseconds

Physicists observe how electron-hole pairs drift apart at ultrafast speed, but still remain strongly bound.

Modern electronics relies on ultrafast charge motion on ever shorter length scales. Physicists from Regensburg and Gothenburg have now succeeded in resolving a...

Im Focus: Researchers 3D print metamaterials with novel optical properties

Engineers create novel optical devices, including a moth eye-inspired omnidirectional microwave antenna

A team of engineers at Tufts University has developed a series of 3D printed metamaterials with unique microwave or optical properties that go beyond what is...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Revered mathematicians and computer scientists converge with 200 young researchers in Heidelberg!

17.04.2019 | Event News

First dust conference in the Central Asian part of the earth’s dust belt

15.04.2019 | Event News

Fraunhofer FHR at the IEEE Radar Conference 2019 in Boston, USA

09.04.2019 | Event News

 
Latest News

New automated biological-sample analysis systems to accelerate disease detection

18.04.2019 | Life Sciences

Explosion on Jupiter-sized star 10 times more powerful than ever seen on our sun

18.04.2019 | Physics and Astronomy

New eDNA technology used to quickly assess coral reefs

18.04.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>