Nav: Home

Autoimmune disease discovery could spark new treatments

November 20, 2017

University of Colorado Boulder researchers have discovered a potent, drug-like compound that could someday revolutionize treatment of rheumatoid arthritis and other autoimmune diseases by inhibiting a protein instrumental in prompting the body to start attacking its own tissue.

"We have discovered a key to lock this protein in a resting state," said Hang Hubert Yin, a biochemistry professor in the BioFrontiers Institute and lead author of a paper, published today in Nature Chemical Biology, describing the discovery. "This could be paradigm shifting."

More than 23.5 million Americans suffer from autoimmune diseases like rheumatoid arthritis, scleroderma and lupus, in which an overzealous immune response leads to pain, inflammation, skin disorders and other chronic health problems.

Three of the top five selling drugs in the United States aim to ease their symptoms. But no cure exists, and treatments are expensive and come with side effects.

"Given the prevalence of these diseases, there is a big push for alternatives," Yin said.

For years, scientists have suspected that a protein called Toll-like receptor 8 (TLR8) plays a key role in the innate immune response. When it senses the presence of a virus or bacteria, it goes through a series of steps to transform from its passive to active state, triggering a cascade of inflammatory signals to fight off the foreign invader. But, as Yin explained, "it can be a double-edged sword" leading to disease when that response is excessive.

Because TLR8 has a unique molecular structure and is hidden inside the endosome -- an infinitesimal bubble inside the cell -- rather than on the cell's surface, it has proven an extremely difficult target for drug development.

"This is a long-sought-after target with very little success," Yin said.

But his study shows a drug-like molecule called CU-CPT8m binds to and inhibits TLR8 and exerts "potent anti-inflammatory effects" on the tissue of patients with arthritis, osteoarthritis and Still's disease, a rare autoimmune illness.

For the study, Yin and his co-authors used high-throughput screening to look through more than 14,000 small molecule compounds to determine whether they had the right chemical structure to bind to TLR8. They identified four that shared a similar structure.

Using that structure as a model, they chemically synthesized hundreds of novel compounds in an effort to find one that perfectly bound to and inhibited TLR8.

Previous efforts to target the protein have focused on shutting it down when it is in its active state. But the compound Yin discovered prevents it from activating while still in its passive state.

"Before, people were trying to close the open door to shut it down. We found the key to lock the door from the inside so it never opens," Yin said.

Much more research is necessary, but that could lead to treatments that strike at the root cause of autoimmune diseases, rather than just treating symptoms.

With help from CU's Technology Transfer Office, Yin has already filed a patent application and hopes to move on to animal studies and clinical trials within the next two years.

In the meantime, the new compound can serve as a first-of-its kind tool to understand exactly what TLR8 and the other nine toll-like receptors do in the body.

"Our study provides the first small molecule tool to shut this protein down so we can understand its pathogenesis," Yin said.
-end-
The National Institutes of Health funded the study.

Researchers from the University of Tokyo, Tsinghua University and Peking Union Medical College Hospital in Beijing contributed to the study.

University of Colorado at Boulder

Related Rheumatoid Arthritis Articles:

Is rheumatoid arthritis two different diseases?
While disease activity improves over time for most rheumatoid arthritis (RA) patients, long-term outcomes only improve in RA patients with autoantibodies, according to a new study published this week in PLOS Medicine by Xanthe Matthijssen of Leiden University Medical Center, Netherlands, and colleagues.
Does the Mediterranean diet protect against rheumatoid arthritis?
Previous research has demonstrated a variety of health benefits associated with the Mediterranean diet, which is rich in olive oil, cereals, fruit and vegetables, fish, and a moderate amount of dairy, meat, and wine.
Reducing corticosteroid use in rheumatoid arthritis
Is the long-term use of glucocorticoids essential in people with chronic inflammatory diseases such as rheumatoid arthritis, or can early discontinuation prevent characteristic side effects?
Rheumatoid arthritis patients under treatment with methotrexate
Patients with rheumatoid arthritis (RA) often suffer from what is referred to as interstitial lung disease (ILD).
Rheumatoid arthritis -- can its onset be delayed or prevented?
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that leads to significant health issues as well as high treatment costs.
Disease burden in osteoarthritis is similar to rheumatoid arthritis
Osteoarthritis (OA) has traditionally been viewed as a highly prevalent but milder condition when compared with rheumatoid arthritis (RA), and some may believe that it is part of a normal aging process requiring acceptance, not treatment.
Prospect of a new treatment for rheumatoid arthritis
An international research group led by Charité -- Universitätsmedizin Berlin has completed testing a new drug to treat rheumatoid arthritis.
Can rare lymphocytes combat rheumatoid arthritis?
Immunologists at Friedrich-Alexander-Universität Erlangen-Nürnberg have demonstrated that ILC2, a group of rare lymphoid cells, play a key role in the development of inflammatory arthritis.
How environmental pollutants and genetics work together in rheumatoid arthritis
New research documents how chemicals and a certain gene activate an enzyme to increase the risk and severity of RA and bone destruction.
Rheumatoid arthritis meets precision medicine
Scientists are bringing precision medicine to rheumatoid arthritis for the first time by using genetic profiling of joint tissue to see which drugs will work for which patients, reports a new multi-site study.
More Rheumatoid Arthritis News and Rheumatoid Arthritis Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.