Mapping out new routes to treat brain disorders

June 20, 2022
Mapping the structure of proteins may help pinpoint brain disorders by testing NMDA levels.

Cold Spring Harbor Laboratory (CSHL) Professor Hiro Furukawa takes an architectural approach to brain research by creating structural 3D maps of important proteins that malfunction in brain disorders, according to a news release.

Furukawa has zeroed in on a protein called the NMDA (for N-methyl-D-aspartate) receptor that plays a key role in learning and memory. The NMDA receptor acts as a channel to allow ions into neurons to activate them. When the NMDA receptor doesn’t work properly, neurons can fire at the wrong times, which can result in disorders like Alzheimer’s disease, depression, and epilepsy.

The Furukawa lab’s maps provide a unique, atomic point of view of the NMDA receptor. They let his team look, in 3D, at how the protein’s atoms are arranged and move. Knowing the precise details of NMDA’s structure allows scientists to develop and optimize therapeutics from new angles.

“We’re trying to essentially provide a blueprint for optimizing drugs that have the potential to treat disorders but [currently] cause dangerous side effects,” Furukawa says. Drugs that fit and match up perfectly to the NMDA receptor or channel could have more benefits and fewer side effects.

Using these maps, Furukawa and his team have innovated two new routes for optimizing NMDA therapeutics. One is to pinpoint the perfect spot where drugs should bind to minimize side effects. Their second approach looks at how well drugs bind to the NMDA channel to maximize their impact.

Most drugs for neurological disorders like Alzheimer’s suffer from severe side effects because they don’t fit just right. They don’t bind well enough to the NMDA receptor and set off unwanted reactions. Furukawa and his team recently used their detailed maps of the NMDA receptor structure to design a molecule that fits perfectly.

The team developed antibodies, or “picky proteins,” that may avoid unwanted side effects by being very picky about what they target. It is designed to bind to a specific spot on the NMDA receptor. When the picky protein binds, it restricts the receptor’s movement and helps close its ion channel. This prevents too many ions from getting through and neurons from activating at the wrong times.

Furukawa and his team are now optimizing the design of the picky protein to improve its potential and efficacy for clinical use. Their work was published in the journal Nature Communications.

While pinpointing the perfect spot for a drug to bind has its advantages, drugs must also stay bound long enough to have a beneficial effect. Furukawa and his team leveraged their blueprints to explore this second route for optimizing therapeutics using three psychotropic drugs. These drugs affect behavior, mood, thoughts, or perception.

The team looked at the binding properties of two FDA-approved drugs, ketamine and memantine. In an unconventional move, they also looked at the recreational drug PCP. Developed in 1959, PCP can cause hallucinations and symptoms akin to schizophrenia. With the help of their atomic maps, the team showed that PCP remained attached the longest. It also blocked the function of the NMDA receptor the best, followed by ketamine and memantine. “This may explain why PCP has more robust psychotic side effects than the other drugs,” says Furukawa.

The team is working on understanding what allows PCP and the other drugs to bind differently. This may help guide the development and improvement of therapeutics to treat brain disorders.

Although Furukawa and his team are focused on the small details of the NMDA receptor, he hopes his work has a much bigger, long-term impact on brain health. “Currently available drugs for Alzheimer’s disease are only effective for a short period of time,” he says. “We want to help to develop reagents that boost cognition for a longer period of time in the order of multiple years.”

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