Drugs Could Be Ferried Across the Blood-Brain Barrier Using an Omega-3 Transporter

Drugs that have trouble crossing the blood-brain barrier could fit into the hold of a molecular ferry called a major facilitator superfamily domain containing 2A (MFSD2A). MFSD2A delivers omega-3 fatty acids into the brain normally. Scientists at Columbia University believe that now that the three-dimensional structure of MFSD2A has been identified, medications that are compatible with the transporter's characteristics can be designed. The impassable would become, well, passable in the presence of such medications.

The three-dimensional structure of omega-3s binding to the transporter was characterized using single-particle cryo-electron microscopy. Rosemary J. Cater, PhD, a research fellow in the Columbia University group led by Filippo Mancia, PhD, an associate professor of physiology and cellular biophysics, said, “This information may allow the design of pharmaceuticals that resemble omega-3s to hijack this system and get into the brain.”

Cater is the study's initial author, and Mancia is the study's senior author. “Structural basis of omega-3 fatty acid transport across the blood–brain barrier” published in Nature. MFSD2A has 12 transmembrane helices divided into two pseudosymmetric domains, according to this study.

The authors of the study noted, "The transporter is in an inward-facing conformation with a huge amphipathic cavity that contains the Na+-binding site and a bound lysolipid substrate, which we validated using native mass spectrometry." “This structure shows details of how MFSD2A interacts with substrates and how Na+-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate, in combination with our functional investigations and molecular dynamics simulations.”

The findings could “provide a framework for the structure-based design of neurotherapeutic medicines that hijack MFSD2A for transport across the blood-brain barrier, which is currently a key bottleneck in the development of neurotherapeutic drugs,” according to the researchers.

The blood-brain barrier is a layer of densely packed cells that lines the blood arteries in the brain and vigorously prevents poisons, infections, and some nutrients from entering. Unfortunately, the layer also prevents many medications from being tested as potential treatments for neurological illnesses.

Dedicated transporter proteins, such as MFSD2A, are required for essential nutrients like omega-3s. “Like bouncers at a bar, the transporters only let molecules in with invites or backstage passes,” Cater added.

“Knowing what MFSD2A looks like and how it transports omega-3s across the blood-brain barrier could provide us the information we need to create medications that can fool this bouncer and get admission passes.”

Cater utilized a method called single-particle cryo-electron microscopy to visualize MFSD2A. (cryo-EM).

“The beauty of this technology is that we can observe the shape of the transporter down to a billionth of a meter in detail,” Mancia explained. “Understanding how the transporter operates at a molecular level requires this information.”

Protein molecules are suspended in a thin layer of ice under an electron microscope for cryo-EM investigation. Millions of photos of the proteins are taken from numerous angles by powerful cameras, which are then put together to create a 3D map.

Researchers can use this information to create a 3D model of the protein, placing each atom in its proper location. Mancia noted, "It reminds me of putting together a jigsaw puzzle."

Thanks in part to Joachim Frank, PhD, professor of biochemistry and molecular biophysics at Columbia University Vagelos College of Physicians and Surgeons, who won the Nobel Prize in 2017 for his role in developing cryo-EM data analysis algorithms, this technique has become remarkably powerful in visualizing biological molecules in recent years.

Cater added, "Our structure demonstrates that MFSD2A has a bowl-like shape and that omega-3s bind to a specific side of this bowl. “The bowl is turned inside out and faces the cell's interior, but this is simply a single 3D photo of the protein, which must move in real life to deliver the omega-3s. We'll need many photos or, better yet, a movie of the transporter in action to figure out exactly how it works.”