Researchers derive first ever molecular model of critical blood-brain barrier transporter.
Presently, there are limitations to drug delivery to the brain as it is tightly protected by the blood-brain barrier. The blood-brain barrier is a protective barrier which separates the circulating blood from the central nervous system which can prevent the entry of certain toxins and drugs to the brain. This restricts the treatment of many brain diseases. Now, researchers from Duke-NUS Medical School (Duke-NUS) have derived a structural model of a transporter at the blood-brain barrier called Mfsd2a, the first ever molecular model of this critical transporter. The team state that their findings could prove important for the development of therapeutic agents that need to be delivered to the brain, across the blood-brain barrier and in future, this could help treat neurological disorders such as glioblastoma. The opensource study is published in the Journal of Biological Chemistry.
Earlier studies from the lab identified Mfsd2a as the first ever transporter of sodium-dependent lysophosphatidylcholine (LPC) across the blood-brain barrier. They went on to show that loss of function mutations in human Mfsd2a resulted in severe microcephaly. This research indicated that LPCs are critical for brain growth and function. The current study shows that as a transporter at the blood-brain barrier, Mfsd2a is a potential conduit for drug delivery directly to the brain, thus bypassing the barrier.
The current study used molecular modeling and biochemical analyses of altered Mfsd2a transporters to derive a structural model of human Mfsd2a. Three 3D structural models of human Mfsd2a were derived by homology modelling using MelB- and LacY-based crystal structures, and refined by biochemical analysis. Results show new binding features of the transporter, providing insight into the transport mechanism of Mfsd2a.
Data finding show that these models reveal three unique regions critical for function, an LPC headgroup binding site, a hydrophobic cleft occupied by the LPC fatty acyl tail, and three sets of ionic locks. Results show that these structural features indicate a novel mechanism of transport for LPCs.
The team surmise that their data provides the first glimpse into what Mfsd2a looks like and how it might transport essential lipids across the blood-brain barrier. They go on to add that it also facilitates a structure-guided search and design of scaffolds for drug delivery to the brain via Mfsd2a, or of drugs that can be directly transported by Mfsd2a. For the future, the researchers state that this information is being used to design novel therapeutic agents for direct drug delivery across the blood brain barrier for the treatment of neurological diseases. They conclude that they plan to validate their findings by purifying the Mfsd2a protein in order to further dissect how it functions as a transporter.