SINGAPORE, June 17, 2021 – New details on the structure and function of a transport protein could help researchers develop drugs against neurological diseases that can better cross the blood-brain barrier. The results were published in the journal Nature by researchers from Columbia University’s Vagelos College of Physicians and Surgeons, Duke-NUS Medical School, Weill Cornell Medicine, and colleagues.

Omega-3 fatty acids like docosahexaenoic acid (DHA) are important for the development of the brain and eyes. They are mainly obtained from food sources and are converted by the liver into a lysolipid called lyso-phosphatidylcholine (LPC), which can then cross the blood-brain or blood-retinal barrier from the blood to the brain and retina. These barriers are made by cells lining blood vessels, or endothelial cells, which tightly regulate what goes into these two vital organs.

A protein called “Major Facilitator Superfamily Domain Contains 2A” (MFSD2A) is located on the membrane of these endothelial cells and acts as a molecular gateway that enables DHA to overcome these barriers. How MFSD2A mediates the uptake of lysolipids, which carry omega-3 fatty acids, remained a mystery.

“We set out to determine the structure of MFSD2A to understand how it transports omega-3 essential fatty acids to the brain in the form of LPC,” said Dr. Chua Geok Lin, Senior Research Fellow in Cardiovascular and Metabolic Disease (CVMD) Programs, Duke-NUS, who is co-author of the study. “This is important because MFSD2A is essential for getting omega-3s like DHA across the blood-brain barrier.”

Dr. Rosemary Cater, Simons Foundation Fellow at Columbia University’s Vagelos College of Physicians and Surgeons and lead author of the article, said, “If we knew what MFSD2A looks like, we could solve this puzzle and use the information to develop neurotherapeutic agents that hijack you this molecular gate disguised as omega-3 fatty acid lysolipids – like looking at what a lock looks like in order to design a matching key. “

Dr. Filippo Mancia from Columbia University, Dr. David Silver from Duke-NUS and Dr. George Khelashvili, a composite study led by Weill Cornell Medicine, used leading experts in the field from a number of US research institutes – Columbia University, Weill Cornell Medicine, the New York Structural Biology Center, the University of Chicago and the University of Arizona – and Duke- NUS in Singapore.

To study the structure of MFSD2A, the research team used a special type of electron microscopy, in which samples are cooled to cryogenic temperatures and molecules are viewed on a sub-nanomolar scale in combination with novel biochemical assays. This enabled them to uncover details of the structure of the protein at the atomic level, which were then used to aid in computer simulations that investigated the mechanism by which it worked.

Dr. Mancia, Associate Professor of Physiology and Cellular Biophysics at Columbia University’s Vagelos College of Physicians and Surgeons: “It’s extremely exciting to see the shape of a protein with such resolution. We’re talking about measurements less than a billionth of a meter tall – and this information is critical to understanding how it works at the molecular level. ”

“With large-scale atomistic ensemble molecular dynamics (MD) simulations, followed by a detailed analysis of the MD data using advanced computational biophysics methods such as Markov State Modeling, we were able to examine the cryo-EM structure of MFSD2A and investigate mechanistic Details of how this transporter interacts with substrates, “explained Dr. Khelashvili, Assistant Professor of Physiology and Biophysics at Weill Cornell Medicine.” In combination with the functional data, the computer results provide information about the molecular mechanisms by which this atypical MFS transporter takes up single-chain phospholipids are conveyed into the brain. “

“A few years ago we discovered that human mutations in the gene that codes for MFSD2A lead to microcephaly, a birth defect in which the baby’s head is very small,” said Dr. Silver, professor and associate director of the Duke-NUS CVMD program. “This underscores the importance of lysolipid transport by MFSD2A.”

The study is the latest addition to the growing body of knowledge first initiated by Prof. Silver in 2014 when he published about the discovery of MFSD2A and its role in transporting DHA to the brain. In 2017 he co-founded Travecta Therapeutics, based in Singapore, with the aim of using this knowledge to develop new therapeutics that can be selectively delivered with MFSD2A across the blood-brain barrier for the treatment of diseases of the central nervous system and the eyes . Travecta is currently in pre-clinical trials for multiple therapeutic targets, with TVT-004, the company’s lead pain agent, scheduled to begin clinical trials in the next several months.

A licensing agreement between Duke-NUS and Travecta was made possible through the Duke-NUS Center for Technology and Development under the School’s Innovation and Entrepreneurship Office, which grants the company the rights to commercialize research.

“The blood-brain barrier blocks the absorption of about 98 percent of drugs, which limits the treatment of neurological diseases,” said Prof. Silver. “The structural information that we uncovered in our study can be used to better develop neurotherapeutic agents that can be transported by MFSD2A.”

The authors said more research is needed to uncover more details on how MFSD2A mediates the transport of lysolipids across the blood-brain barrier.


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