New discovery may help reduce side effects of MS drugs

March 21, 2022
Investigators from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center have discovered how a drug for multiple sclerosis interacts with its targets, a finding that may pave the way for better treatments.

The study details the precise molecular structure of the MS drug siponimod as it interacts with its target, the human S1P receptor 1, and off-target receptors using an electron microscopy technique called cryo-EM. This knowledge could help scientists develop drugs for the disease that are less likely to miss their targets.

In patients with MS, immune cells called lymphocytes attack and destroy the protective sheath around nerve cells, causing progressive neurologic symptoms. Scientists developed immune-suppressing drugs that block the release of these lymphocytes from the lymph nodes by binding to S1P1 receptors. But the first-generation version of these drugs could also bind to related receptors including S1P3, which caused unwanted side-effects including an abnormal heart rhythm. To address this problem, scientists created next-generation medications such as siponimod that bind more selectively to S1P1 and another receptor called S1P5. But this didn’t eliminate all unwanted side-effects.

The new study reveals how siponimod binds to these two receptors and the features of the molecule that prevent it from binding to unwanted targets such as S1P2, S1P3, and S1P4. Scientists can use this information to modify the drug to help it attach more tightly to its target, S1P1, and less likely to bind with unintended target, S1P5, reducing the risk of side-effects.

The study was published in the journal Nature Communications.

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