Inflammatory responses to injury or disease are crucial for recruiting the immune system to help the body heal, but inflammation can also cause an increase in the production of thrombin, which can lead to dangerous blood clots and other conditions. Now, researchers are reporting in the Proceedings of the National Academy of Sciences that a class of small molecules called parmodulins may be able to reduce inflammation without compromising normal blood clotting, making them attractive candidates for new, safer drugs.
Activated protein C (APC) is a naturally occurring anti-coagulant protein with anti-inflammatory and other protective effects that has been used for treating severe blood infections and wounds. However, its use is limited because its inhibition of thrombin also impacts the blood's ability to clot. A team of researchers from Beth Israel Deaconess Medical Center (BIDMC) and the Wyss Institute at Harvard University now have discovered that parmodulins, which are synthetic APC-mimicking small molecules, provide anti-inflammatory and anti-thrombotic protection to endothelial cells on par with APCs without interfering with normal blood clotting and coagulation.
“APC had been used for nearly a decade in the setting of sepsis because of its anti-inflammatory effect. However, its dosing was limited by its anti-coagulant activity. We have now circumvented this problem by using a small molecule that activates the cytoprotective pathway, but does not have APC's anti-coagulant effects,” said study co-author Rob Flaumenhaft, MD, PhD, who is a professor of medicine at Harvard Medical School and Chief of the Division of Hemostasis and Thrombosis at BIDMC in Boston, Massachusetts.
Organ-on-a-Chip technology was key to making this new discovery. Whole blood was perfused through a chip to simulate the flow conditions within human blood vessels. Pro-inflammatory and anti-inflammatory compounds were added to evaluate the response of the endothelium.
The target protein on which both APC and parmodulins act is the transmembrane protein protease-activated receptor 1 (PAR1), which is present on both endothelial cells and platelets that circulate through the blood and promote clotting. “It is amazing that a small pharmacological agent can replicate the same anti-inflammatory pathway that typically requires a complex association of proteins to accomplish. What's more, this small molecule achieves this feat by acting at the cytosolic side of a G-protein coupled receptor,” Dr. Flaumenhaft told Cancer Network.
A series of in-vitro tests confirmed that parmodulin-2 activation of PAR1 also induces cytoprotective responses in endothelial cells. In addition, in-vivo studies in mice showed that parmodulin-2 reduces the binding of white blood cells to blood vessels and impairs platelet and fibrin accumulation at injury sites during the inflammatory response. “Our next step is to optimize analogs with the same mechanism of action to develop a compound with favorable pharmacokinetics and pharmacodynamics for therapeutic use in humans,” said Dr. Flaumenhaft.