Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New compounds could be used to treat autoimmune disorders

29.05.2019

The immune system is programmed to rid the body of biological bad guys--like viruses and dangerous bacteria--but its precision isn't guaranteed. In the tens of millions of Americans suffering from autoimmune diseases, the system mistakes normal cells for malicious invaders, prompting the body to engage in self-destructive behavior. This diverse class of conditions, which includes Type I diabetes, lupus, and multiple sclerosis, can be very difficult to treat.

In a new report in Nature Communications, researchers in the laboratory of Thomas Tuschl describe their development of small molecules that inhibit one of the main enzymes implicated in misguided immune responses. This research could lead to new treatments for people with certain autoimmune disorders and, more broadly, sheds light on the causes of autoimmunity.


Newly-developed molecules bind to a key enzyme pocket to inhibit its activity, and possibly prevent autoimmune responses.

Credit: Laboratory of RNA Molecular Biology at The Rockefeller University

Usage Restrictions: Image may be used to illustrate the research described in the accompanying release.

Cellular security

In eukaryotes, including humans, DNA typically resides in a cell's nucleus, or in other sequestered organelles such as mitochondria. So if DNA is found outside of these compartments--in the cell's cytosol--the immune system goes into high alert, assuming the genetic material was leaked by an invading bacterium or virus.

In 2013, researchers discovered an enzyme called cyclic GMP-AMP synthase, or cGAS, that detects and binds to cytosolic DNA to initiate a chain reaction--a cascade of cellular signaling events that leads to immune activation and usually ends with the destruction of the DNA-shedding pathogen.

Yet, cytosolic DNA isn't always a sign of infection. Sometimes it's produced by the body's own cells--and cGAS does not discriminate between infectious and innocuous DNA. The enzyme will bind to perfectly harmless genetic material, prompting an immune response even in the absence of an intruder.

"There is no specificity. So in addition to sensing foreign microbial DNA, cGAS will also sense aberrant cytosolic DNA made by the host," says postdoctoral associate Lodoe Lama. "And this lack of self versus non-self specificity could be driving autoimmune reactions."

Since the discovery of cGAS, researchers in the Tuschl laboratory have sought to understand its potential clinical relevance. If autoimmune disorders are the result of an erroneously activated immune system, then perhaps, they believe, a cGAS inhibitor could be used to treat these conditions.

Until now, no potent and specific small-molecule compound existed to block cGAS in human cells, though the researchers previously identified one that can do the job in mouse cells. Hoping to fill this gap, Tuschl's team collaborated with Rockefeller's High-Throughput and Spectroscopy Resource Center to scan through a library of almost 300,000 small molecules, searching for one that might target human cGAS.

Building a blocker

Through their screen, the researchers identified two molecules that showed some activity against cGAS--but this result was just the beginning of a long process towards developing an inhibitor that might be used in a clinical setting.

"The hits from library compounds were a great starting point, but they were not potent enough," says Lama. "So we used them as molecular scaffolds on which to make improvements, altering their structures in ways that would increase potency and also reduce toxicity."

Working with the Tri-Institutional Therapeutics Discovery Institute, the researchers modified one of their original scaffolds to create three compounds that blocked cGAS activity in human cells--making them the first molecules with this capability. Further analysis by researchers at Memorial Sloan Kettering Cancer Center revealed that the compounds inhibit cGAS by wedging into a pocket of the enzyme that is key to its activation.

The compounds are now being further optimized for potential use in patients, with an initial focus on treatment of the rare genetic disease Aicardi-Goutières syndrome. People with this condition accumulate abnormal cytosolic DNA that activates cGAS, leading to serious neurological problems. A drug that blocks the enzyme would therefore be of tremendous therapeutic value to those with the disease, who currently have few treatment options.

"This class of drug could potentially also be used to treat more common diseases, such as systemic lupus erythematosus, and possibly neurodegenerative diseases that include inflammatory contributions, such as Parkinson's disease," says Tuschl.

Further, the researchers believe that these compounds could serve as practical laboratory tools.

"Scientists will now have simple means by which to inhibit cGAS in human cells," says Lama. "And that could be immensely useful for studying and understanding the mechanisms that lead to autoimmune responses."

Media Contact

Katherine Fenz
kfenz@rockefeller.edu
212-327-7913

 @rockefelleruniv

http://www.rockefeller.edu 

Katherine Fenz | EurekAlert!
Further information:
https://www.rockefeller.edu/news/25972-new-compounds-used-treat-autoimmune-disorders/
http://dx.doi.org/10.1038/s41467-019-08620-4

More articles from Life Sciences:

nachricht Gold nanoclusters: new frontier for developing medication for treatment of Alzheimer's disease
17.02.2020 | Science China Press

nachricht Catalyst deposition on fragile chips
17.02.2020 | Ruhr-University Bochum

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Freiburg researcher investigate the origins of surface texture

Most natural and artificial surfaces are rough: metals and even glasses that appear smooth to the naked eye can look like jagged mountain ranges under the microscope. There is currently no uniform theory about the origin of this roughness despite it being observed on all scales, from the atomic to the tectonic. Scientists suspect that the rough surface is formed by irreversible plastic deformation that occurs in many processes of mechanical machining of components such as milling.

Prof. Dr. Lars Pastewka from the Simulation group at the Department of Microsystems Engineering at the University of Freiburg and his team have simulated such...

Im Focus: Skyrmions like it hot: Spin structures are controllable even at high temperatures

Investigation of the temperature dependence of the skyrmion Hall effect reveals further insights into possible new data storage devices

The joint research project of Johannes Gutenberg University Mainz (JGU) and the Massachusetts Institute of Technology (MIT) that had previously demonstrated...

Im Focus: Making the internet more energy efficient through systemic optimization

Researchers at Chalmers University of Technology, Sweden, recently completed a 5-year research project looking at how to make fibre optic communications systems more energy efficient. Among their proposals are smart, error-correcting data chip circuits, which they refined to be 10 times less energy consumptive. The project has yielded several scientific articles, in publications including Nature Communications.

Streaming films and music, scrolling through social media, and using cloud-based storage services are everyday activities now.

Im Focus: New synthesis methods enhance 3D chemical space for drug discovery

After helping develop a new approach for organic synthesis -- carbon-hydrogen functionalization -- scientists at Emory University are now showing how this approach may apply to drug discovery. Nature Catalysis published their most recent work -- a streamlined process for making a three-dimensional scaffold of keen interest to the pharmaceutical industry.

"Our tools open up whole new chemical space for potential drug targets," says Huw Davies, Emory professor of organic chemistry and senior author of the paper.

Im Focus: Quantum fluctuations sustain the record superconductor

Superconductivity approaching room temperature may be possible in hydrogen-rich compounds at much lower pressures than previously expected

Reaching room-temperature superconductivity is one of the biggest dreams in physics. Its discovery would bring a technological revolution by providing...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

70th Lindau Nobel Laureate Meeting: Around 70 Laureates set to meet with young scientists from approx. 100 countries

12.02.2020 | Event News

11th Advanced Battery Power Conference, March 24-25, 2020 in Münster/Germany

16.01.2020 | Event News

Laser Colloquium Hydrogen LKH2: fast and reliable fuel cell manufacturing

15.01.2020 | Event News

 
Latest News

Gold nanoclusters: new frontier for developing medication for treatment of Alzheimer's disease

17.02.2020 | Life Sciences

Artificial intelligence is becoming sustainable!

17.02.2020 | Information Technology

Catalyst deposition on fragile chips

17.02.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>