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The team has developed a highly selective protein-based biologic called a nanobody that targets a newly discovered brain receptor implicated in depression. When delivered in preclinical models, this nanobody produced fast, lasting antidepressant effects, offering a potential new therapeutic pathway for one of the world’s most pervasive mental health disorders.

Targeting a Newly Identified Receptor in the Brain

Major depressive disorder is common, but many available treatments work slowly or fail to help a number of patients. Known as treatment resistant depression, the condition leaves millions of people stranded without adequate solutions. 

Recently, scientists identified mGlyR (short for metabotropic glycine receptor) as a key player in depression biology. This receptor is highly active in the prefrontal cortex, a brain region responsible for decision-making and emotional control. In people diagnosed with depression, mGlyR levels are elevated. Likewise, pre-clinical models engineered to lack mGlyR show increased stress resilience and reduced depression-like behaviors.

Because traditional small‑molecule drugs have trouble precisely targeting receptors like mGlyR, Dr. Martemyanov, recently named professor and chair of the Department of Physiology and Biophysics at the Miller School, explored whether a nanobody could effectively inhibit this receptor. These single‑domain antibodies are small, specific and can reach targets inaccessible to larger biologics.

“Nanobodies have not been traditionally applied for the treatment of nervous system disorders,” said Dr. Martemyanov. “However, this is beginning to change as more evidence supports their penetration into the brain.”

Engineering a Precise Nanobody

To create such a tool, researchers used phage display, a method for selecting single-domain antibodies with strong and specific binding. Out of dozens of candidates, the nanobody Nb20 stood out because it tightly bound to the part of the receptor that detects molecules like glycine.

Lab experiments showed that Nb20 attaches strongly and selectively to mGlyR but not to similar receptors, confirming its precision.

“The use of cryo-electron microscopy (CryoEM) allowed us to glean the fine details of Nb20 engagement with mGlyR and how it changes its structure,” said Dr. Martemyanov, noting that the University of Miami is at the forefront of the CryoEM technology, specifically at the Frost Institute for Chemistry and Molecular Science where Dr. Martemyanov’s laboratory partially resides. “The use of CryoEM offers and an unprecedented opportunity to provide deep molecular insights into the actions of therapeutics potentially transforming drug development.”

How the Nanobody Changes Receptor Signaling

The team next explored how Nb20 changes mGlyR’s function inside cells. mGlyR works in an unusual way, signaling through a protein complex, which helps shut down heterotrimeric G proteins. When this brake is engaged, certain neurons become less excitable, an effect associated with depression-like behaviors in animal models.

Nb20 interferes with this brake. Tests in human cells showed that Nb20 prevents mGlyR from activating the complex, which in turn allows G‑proteins to signal more freely. This higher level of signaling is known to produce antidepressant effects.

CryoEM studies revealed precisely how it is achieved. Nb20 binding causes structural shifts that ripple down from the receptor’s outer surface into its core, altering its shape. These structural changes likely make the protein more flexible and less effective at shutting down G protein signaling.

Rapid Antidepressant Effects

The most striking findings emerged from in vivo studies.

Nb20 showed powerful antidepressant-like behaviors. Nb20 produced rapid antidepressant effects which persisted for at least two weeks after a single treatment, an unusually long duration for a biologic intervention. The effects rivaled those of ketamine, a recently approved antidepressant that carries significant risks of side effects. Remarkably, Nb20 were also effective when delivered by the intranasal route, simply putting it into the nostrils.

The nanobody also normalized stress‑induced increases in corticosterone, a key hormone linked to depression. Electrophysiological studies further showed that Nb20 increased the excitability of neurons in the prelimbic cortex, a region involved in mood regulation.

Implications for Future Treatment

This study is among the first to demonstrate that a biologic directed at a brain target has significant therapeutic efficacy. In the case of this study, a nanobody produced robust antidepressant effects with non‑invasive delivery. If future research confirms similar safety, specificity and efficacy in humans, nanobody‑based therapies could represent an entirely new class of antidepressants capable of rapid onset, high selectivity and improved tolerability.

Next steps include optimizing Nb20 for human use, further assessing potential off‑target effects, improving brain penetration and evaluating long‑term safety, the areas that Dr. Martemyanov’s team is currently pursuing to accelerate bringing the treatments to the clinic. While significant work lies ahead, the current findings offer a promising blueprint for biologic‑based treatments for difficult‑to-treat brain disorders.

“The use of biologics ushers in a new era of developing a completely new class of potent and selective drugs for the treatment of a wide range of brain disorders, which may include a vast array of debilitating neuropsychiatric, neurodevelopmental and neurodegenerative conditions,” said Dr. Martemyanov.

Read the original article on University of Miami.