Navigation Links
Stopping unwanted cell death: Implications for drug discovery
Date:4/13/2008

BOSTON (April 13, 2008, 1:00 p.m. ET) 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 Yuans 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.


'/>"/>

Contact: Siobhan E. Gallagher
siobhan.gallagher@tufts.edu
617-636-6586
Tufts University, Health Sciences
Source:Eurekalert  

Related biology news :

1. Steps toward Stopping Autoimmune Disease
2. From delicious to death: Understanding taste
3. Reflecting on the social implications of human genetics research -- past, present and future
4. Multiple species of bacteria may cause trachoma: Implications for treatment
5. NHGRI funds new Centers for Excellence in Ethical, Legal and Social Implications Research
6. Journey to the center of the earth: Discovery sheds light on mantle formation
7. UC San Diego researchers eliminate drug discovery bottleneck
8. Work with power grids leads to cell biology discovery
9. Surprising discovery from first large-scale analysis of biodiversity and biogeography of viruses
10. International team announces discovery of massive Jurassic marine reptile
11. Gene discovery made easier with powerful new networking technique
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Stopping unwanted cell death: Implications for drug discovery
(Date:6/27/2016)... Research and Markets has announced the addition ... to their offering. The report ... to grow at a CAGR of 12.28% during the period 2016-2020. ... in-depth market analysis with inputs from industry experts. The report covers ... The report also includes a discussion of the key vendors operating ...
(Date:6/22/2016)... American College of Medical Genetics and Genomics was once again ... of the fastest-growing trade shows during the Fastest 50 Awards ... Las Vegas . Winners are ... of the following categories: net square feet of paid exhibit ... 2015 ACMG Annual Meeting was ranked 23 out of 50 ...
(Date:6/22/2016)... 2016   Acuant , the leading ... has partnered with RightCrowd ® to ... Management, Self-Service Kiosks and Continuous Workforce Assurance. ... functional enhancements to existing physical access control ... with an automated ID verification and authentication ...
Breaking Biology News(10 mins):
(Date:6/27/2016)... 2016  Alex,s Lemonade Stand Foundation (ALSF), a leading ... open a state-of-the-art bioinformatics lab, using ,big data, to ... comes as Liz Scott , co-executive director of ... Summit in Washington, D.C. , hosted ... and advocate of pediatric cancer research and awareness. ...
(Date:6/27/2016)...  Global demand for enzymes is forecast to ... $7.2 billion.  This market includes enzymes used in ... production, animal feed, and other markets) and specialty ... and beverages will remain the largest market for ... products containing enzymes in developing regions.  These and ...
(Date:6/27/2016)... , June 27, 2016 /PRNewswire/ - BIOREM Inc. (TSX-V: BRM) ... advised by its major shareholders, Clean Technology Fund I, ... United States based venture capital funds which ... Biorem (on a fully diluted, as converted basis), that ... of their entire equity holdings in Biorem to TUS ...
(Date:6/27/2016)...  Sequenom, Inc. (NASDAQ: SQNM ), a ... the development of innovative products and services, announced today ... States denied its petition to review decisions ... U.S. Patent No. 6,258,540 (",540 Patent") are not patent ... Supreme Court,s Mayo Collaborative Services v. Prometheus Laboratories decision.  ...
Breaking Biology Technology: