Paving the way for new drugs to treat a range of diseases

Turning an integrin ​“off” could be the key to new pharmaceuticals for a wide range of conditions, including multiple sclerosis.

Normally, when our bodies’ immune systems are called to fight off an infection, our defenses go into action as intended. The signaling pathways between our cells that rouse an immune response work as they’re meant to. But in some cases, however, certain proteins in cells can signal a ​“false alarm” that causes a variety of harmful immune responses. These responses are implicated in conditions ranging from inflammatory bowel disease to multiple sclerosis.

Now, however, researchers from Boston Children’s Hospital and Harvard University, who made use of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory, have found a way to design a new class of pharmaceuticals. These drugs could be orally administered, and could help to shut off the ​“false alarm” and potentially help address these and other conditions, such as thrombosis and cancer.

The Harvard team, led by professor Timothy Springer and first author Fu-Yang ​“Albert” Lin, now of Morphic Therapeutic, looked at a particular kind of cell surface receptor called integrins, which help allow cells to attach to other areas of the body, or to one another.

Springer recently won a Lasker Award, a major medical prize, for his contributions to discovering and characterizing the functions of integrins.

According to Lin, immune cells use integrins to adhere to inflamed tissues. When cells are infected or under inflammatory stress, they present ligands that the integrin recognizes, like a firefighter rushing to the area where there’s smoke. ​“The ligand and other chemicals signal to the integrin on the immune cells that says, ​‘Hey, there’s a problem, you need to stop here and address it’,” Lin said.

In autoimmune diseases such as multiple sclerosis, the ligands are put out even though there’s no underlying infection, triggering the immune response and the activation of the integrins. Researchers have been trying to find orally administered therapeutics that effectively suppress the activity of the integrins so that they do not attach to the ligand, preventing the overreacting immune response.

However, most of these earlier generation compounds actually made patients worse, not better. The paradoxical effects of oral integrin therapeutics seen in the clinic have troubled researchers in the field for decades. Now, the Harvard team thinks they figured out how to get around the problem.

To find a broad class of molecules that could do this, the researchers have been using the GM/CA beamline at the APS for over a decade to characterize crystal structures of the integrin with more than twenty different compounds.

They found that integrins can have two different configurations: an open ​“on,” or activated position, and an ​“off” position, depending on the characteristics of the compounds they are associated to. When the integrin is in its ​“on” position, it likely contributes to the worsening effects of prior generation drugs.

“The key is to keep the integrin in its ​‘off’ state,” Lin said.

When a compound stabilizes the integrin in the ​“off” position, it holds a tightly bound water molecule that prevents integrin activation. Springer named this new class of compounds ​“closure-stabilizing integrin inhibitors.”

While antibody drugs targeting integrins have been developed to help patients with serious diseases, Lin, Springer and their teams wanted to develop drugs that could be administered by mouth. Previous oral drugs that had been developed to fight against a number of conditions actually caused activation of the integrins rather than keeping them in the ​“off” position, Lin said.

The way the new class of molecules work is by getting in between the ligand and the integrin, competing with the binding process. At the same time, they help to switch the shape of the integrin receptor back to its ​“off” state.

“The beauty of our finding is that the chemical principle we identified is general to integrins,” Lin said. ​“One can simply design compounds that hold tightly to the water molecule and prevent integrins from binding to the ligand by stabilizing the ​‘off’ state, rendering it inactivated.”

According to Lin, the research points to a way to fashion a whole new class of orally administered compounds that could be more efficacious against a host of different conditions.

A paper based on the study was published in Cell on Sept. 15.

The work was funded by DOE’s Office of Science, Basic Energy Sciences program and the National Institutes of Health.

About the Advanced Photon Source

The U. S. Department of Energy Office of Science’s Advanced Photon Source (APS) at Argonne National Laboratory is one of the world’s most productive X-ray light source facilities. The APS provides high-brightness X-ray beams to a diverse community of researchers in materials science, chemistry, condensed matter physics, the life and environmental sciences, and applied research. These X-rays are ideally suited for explorations of materials and biological structures; elemental distribution; chemical, magnetic, electronic states; and a wide range of technologically important engineering systems from batteries to fuel injector sprays, all of which are the foundations of our nation’s economic, technological, and physical well-being. Each year, more than 5,000 researchers use the APS to produce over 2,000 publications detailing impactful discoveries, and solve more vital biological protein structures than users of any other X-ray light source research facility. APS scientists and engineers innovate technology that is at the heart of advancing accelerator and light-source operations. This includes the insertion devices that produce extreme-brightness X-rays prized by researchers, lenses that focus the X-rays down to a few nanometers, instrumentation that maximizes the way the X-rays interact with samples being studied, and software that gathers and manages the massive quantity of data resulting from discovery research at the APS.

This research used resources of the Advanced Photon Source, a U.S. DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.

Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science.

The U.S. Department of Energy’s Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit https://​ener​gy​.gov/​s​c​ience.