Investigators at Theill Cornell MedicineandMemorial Sloan Kettering Cancer Center have discovered how a medication for multiple sclerosis interacts with its targets, paving the way for better treatment.
The study, published on February 8, reveals the exact molecular structure of the multiple sclerosis drug siponimod as it interacts with its target, the human S1P receptor 1 (S1P1), and off-target receptors, using a cutting-edge electron microscopy technique called cryo-EM. This knowledge would help scientists develop drugs for the disease that are less likely to miss their targets.
Using this information, we can improve therapies for multiple sclerosis and reduce their side effects, according to the co-senior author Dr. Xin-Yun Huang, a professor of physiology and biophysics at Weill Cornell Medicine.
immune cells called lymphocytes damage and destroy the protective sheath around nerve cells, causing serious neurologic symptoms. Scientists developed immune-suppressing drugs that blocked the release of these lymphocytes from the lymph nodes by binding to S1P3, which also caused unwanted side effects. However, the first-generation drugs, like siponimod, could also bind to S1P3, which also caused an abnormal heart rhythm. This didn''t eliminate all of these other limitations.
The new study, led by Dr. Shian Liu, a research associate at Weill Cornell Medicine, and Navid Paknejad, a graduate student at Memorial Sloan Kettering, reveals how siponimod binds to these two receptors and the features of the molecule that prevents it from binding to unwanted targets like S1P2, S1P3, and S1P4. Scientists can also use this information to modify the medication to help it attach more tightly to its target (S1
Dr. Huang said this new structural information will help develop the next generation of multi-sclerosis drugs.
The study also explains how naturally occurring lipids can regulate the immune system, the nervous system, and lung function. Several experiments found that almost identical lipids called sphingosine 1-phosphate and lysophosphatidic acid grew in many directions when linked to their target receptors.
Lipids are highly plastic molecules, and the structures reveal how receptors leverage subtle differences in the lipids structures to discriminate between them, according to the co-senior authorDr. Richard Hite, a structural biologist at Memorial Sloan Kettering and an assistant professor in biochemistry and structural biology and the physiology, biophysics and systems biology programs at the Weill Cornell Graduate School of Medical Sciences.
Interestingly, the findings suggest that lipids may play very different roles in the body, even if their chemical structures are very similar.
lipid-based drugs must be carefully developed to prevent them from reaching their targets, according to the study. We need to make lipid-based drugs that are very specific to reduce the risk of side effects.
These new insights might assist scientists develop improved treatment for other autoimmune diseases, such as inflammatory bowel disease, psoriasis, and systemic lupus. They might also assist researchers in developing lipid-based therapies for conditions that affect the brain or lungs. For example, Dr. Huang said that there are currently lipid-based drugs in clinical trials to decrease lung stiffening in patients with COVID-19.