Discovery of Drug-Like Compound May Change How Autoimmune Diseases are Treated

Discovery of Drug-Like Compound May Change How Autoimmune Diseases are Treated

By Staff.

The discovery of a potent, drug-like compound has researchers thinking it may revolutionize the treatment of rheumatoid arthritis and other autoimmune diseases. It works by inhibiting a protein that is instrumental to triggering 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 in Nature Chemical Biology, describing the discovery. “This could be paradigm shifting.”

More than 23 million Americans suffer from autoimmune diseases like rheumatoid arthritis, scleroderma and lupus, where an overenthusiastic immune response leads to pain, inflammation, skin disorders and other chronic health problems.

Three of the top five selling drugs are designed to ease their symptoms, but no cure exists. These 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 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.

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Authored by: Staff

There are 5 comments for this article
  1. Julie C. at 1:30 pm

    Kathy C:

    I am a perfect, living-proof, example [“guinea pig”] that “Pharma has been advertising a series (of) these Immuno-suppresant “Biologics” as if they are the ‘Cure.’ The Side Effects sound pretty terrifying.“ In my experience, the side effects have been profoundly terrifying!

    Over the course of 3 years I received 5 Biologics, under a maximum trial duration of 3 month’s [since any longer would have left me unable to type this comment]. One was taken in combination with Methotrexate and the remaining 4 without.

    It was my pain management physician who recently pointed out that after each and every Biologic trial I suffered through, the increase in both side-effects and my RA disease activity, was leaving me “worse for wear”. . . worse health than before each subsequent trial.

    The most recent one left me close to kidney failure, despite being a relatively “healthy” 45 year-old woman otherwise.

    I look forward to the day when treatments for Rheumatoid Arthritis exist that actually work toward “fixing” my faulty immune system, rather than all of these heavily publicized and overwhelmingly advertised “poisons” (at least for me) that claim they slow the progression of symptoms/disease. For many, especially me, our experience is that the side-effects alone leave us with a much lower quality of life while receiving them versus not receiving them at all.

  2. Karen Augustine at 5:06 pm

    I now suffer with five, yes five autoimmune disorders, including RA. This article brought tears to my eyes. Thank you for posting this. I never miss an article.

  3. Kathy C at 9:20 am

    This sounds great, but it is much to early to make any kind of educated guess to whether this might apply to anything. It is rather irresponsible to even reprint any of these “Studies.” The only way to evaluate any of this would be to look at the thousands of other “Studies’ and Research. These Articles tend to be selling an idea of “progress” or that there is some kind of sense to the current utter Lack of Science.
    Pharma has been advertising a series so these Immuno-suppresant “Biologics” as if they are the “Cure.” The Side Effects sound pretty terrifying. The average patient has no way of evaluating, any of the claims made in these Advertisements, nor do their Doctors. all they have to do is downplay the risks, and put few cherry picked number sin the advertisements and they can make billions. These kinds of Articles only tend to hide the Facts, and give the false idea that any of this makes sense. The Keyword is “May” they can make any kind of misleading and deceptive claim about this “Research” as long as they use the word “May.”

  4. HJ at 6:47 am

    This is so desperately needed. My mother and I both have osteoarthritis and I nearly didn’t finish reading the article because I thought it may only apply to rheumatoid arthritis. So many possibilities… at a time when drugs for symptom management are being restricted.

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