Insights from new study may lead to safer drugs

BOSTON – Integrins are receptors on the surface of the cell that contribute to a variety of diseases, including cardiovascular disease, diabetic kidney disease, multiple sclerosis, nonalcoholic liver disease, inflammatory bowel disease and brain cancer. Unfortunately, drugs developed to block integrins in such diseases have actually been shown to activate these receptors, leading to serious health problems for patients. Now, however, a team led by investigators at Massachusetts General Hospital (MGH) has developed a method to design drugs that efficiently block rather than activate these receptors thus avoiding adverse outcomes. The research is published in Nature Communications.

As an example of a current problem with targeting integrins in patients, the researchers point to the use of drugs such as eptifibatide and tirofiban, which are prescribed to prevent blood clots in patients after heart attacks or during cardiac procedures. These medications are designed to block a specific integrin on platelets but they can also cause unwanted changes that trigger reactions leading to excessive bleeding.

“In our study, we analyzed the structure of this integrin when bound to a ligand and then engineered a stable compound that would bind to the integrin but not trigger its activity—in other words, it effectively blocked the receptor without paradoxically activating it,” said senior author M. Amin Arnaout, MD, an investigator in and former chief of the Division of Nephrology at MGH and a professor of Medicine at Harvard Medical School.

The new drug was as effective as the standard dose of eptifibatide in inhibiting clotting in laboratory and animal tests. And while eptifibatide caused the expected excessive bleeding, the new drug did not.

Arnaout’s team then determined the structure of the drug/integrin complex and used the structure to redesign the small molecule tirofiban into a more effective drug. The modified tirofiban inhibited arterial thrombosis in mice as well as the standard dose of tirofiban, but it did not cause bleeding. “These data provide the first proof of concept that our strategy for targeting integrins may provide safer drug alternatives for human therapy,” said Arnaout.

About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $1 billion and comprises more than 8,500 researchers working across more than 30 institutes, centers and departments. In August 2019 the MGH was once again named #2 in the nation by U.S. News & World Report in its list of "America’s Best Hospitals."