3D Showing of Mayzent Binding to Receptor Could Advance Treatments
For the first time, researchers have brought to light the precise three-dimensional structure of Mayzent (siponimod) as it binds to its molecular target, the sphingosine 1-phosphate receptor 1 (S1P1).
These findings are expected to aid in developing next-generation MS therapeutics with better selectivity for S1P1, enhancing their potency while reducing unwanted side effects, the researchers noted.
“This new structural information will help us develop the next generation of multiple sclerosis drugs,” Xin-Yun Huang, PhD, a professor of physiology and biophysics at Weill Cornell Medicine and a study co-lead author, said in a press release.
The study, “Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate,” was published in the journal Nature Communications.
S1P1 modulators like Mayzent are a class of oral multiple sclerosis (MS) therapies that prevent immune cells from leaving lymph nodes and causing a misguided immune attack in the brain and spinal cord.
Currently, four S1P1 modulators are approved to treat MS: Mayzent, Gilenya (fingolimod), Ponvory (ponesimod), and Zeposia (ozanimod). They all are designed to bind to and activate the S1P1 receptor, but some of these molecules also inadvertently target other sphingosine 1-phosphate receptors.
Gilenya, the first approved S1P1 modulator, can also bind and activate S1P3, resulting in side effects that can include an abnormal heart rhythm. Mayzent was designed to bind to S1P1 more selectively and avoid S1P3, but it interacts with S1P5 and can cause its own side effects.
Understanding how these therapies interact with their target receptors, as well as off-target receptors, at a molecular level can highlight ways to improve medicines to be more specific and potent, with fewer side effects.
Huang and his team set out to determine the molecular structure of the human S1P1 receptor bound to either Mayzent or to its natural ligand, the lipid (fat) molecule sphingosine 1-phosphate (S1P).
For comparison, the researchers also solved the structure of a molecule similar to S1P called lysophosphatidic acid (LPA) bound to its lysophosphatidic acid (LPA1) receptor. These lipid molecules are very similar, though their roles in the body differ markedly.
A technique known as cryo-electron microscopy was applied to reveal the atom-by-atom details of these receptor proteins and their ligands.
The detailed structures showed the S1P1 and LPA1 receptors to have distinct architectures. In S1P1, the region that bound to S1P was a cylindrical-like cavity, while that region was a pouch-like side pocket in LPA1.
Notably, Mayzent was located within the S1P1 cavity and directly interacted with a subsite in the cavity called B1. The adjacent B3 subsite was unoccupied.
“The B3 site discovered in our structures can be further exploited to design drugs to achieve optimized receptor subtype specificity and reduced side effects,” the team wrote.
Based on these different binding site architectures, S1P and LPA, which are very similar in structure, form different shapes when bound to their target receptors. An analysis of the receptors without S1P and LPA, done to examine the changes in structure that occur when they bind their molecules, showed they were activated differently by their ligands.
“Lipids are highly plastic molecules, and the structures reveal how the receptors leverage subtle differences in the lipids structures to discriminate between them,” said Richard Hite, PhD, the study’s other lead author, and a structural biologist at Memorial Sloan Kettering Cancer Center and Weill Cornell.
“This explains how lipids can play very different roles in the body even though their chemical structures are very similar,” Huang added.
Because of similarities in the different types of S1P receptors, the researchers created computer-simulated structures of S1P2, S1P3, S1P4, and S1P5 when bound to Mayzent. Results showed that Mayzent was partly blocked from the binding cavities of S1P2, S1P3 and S1P4, confirming its selectivity to its S1P1 preferred target and to the off-target S1P5.
The researchers noted that the subsites B2 and B3 within the binding cavity in S1P1 and S1P5 were different, and they “could be explored to improve the selectivity for S1P1.” These structural data, as such, can “facilitate the development of next-generation S1P1 selective therapeutics.”
The same mechanism is likely to apply to Zeposia and Ponvory, the researchers added.
“This discovery will help us improve drugs for multiple sclerosis and reduce their side effects,” Huang said. “We need to make lipid-based drugs that are very specific to reduce the risk of side effects.”
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