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<p>Development of therapies for neuropsychiatric conditions is one of the greatest challenges of modern medicine. Common limitations of traditional small molecule drugs include poor efficacy, off-target side effects and difficult druggability of many targets. In this study, we report a different approach deploying small engineered single domain antibodies, known as nanobodies, for the treatment of depression, a prevalent neuropsychiatric condition. We develop highly selective nanobodies for a recently discovered glycine receptor mGlyR crucially linked to pathophysiology of depression. Using a mouse model of stress-induced depression, we show that non-invasive intranasal delivery of nanobody produces rapid and lasting anti-depressant effect. We solve an atomic structure of mGlyR bound to nanobody and use a variety of cell-based approaches to reveal the mechanism of mGlyR modulation and its impact on neural circuitry. These findings support development of biologics for the treatment of intractable brain disorders.</p>

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Targeting mGlyR with nanobodies for depression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月26日

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  • Thibaut Laboute,
  • Stefano Zucca,
  • Omar K. Sial,
  • Mansi Sharma,
  • Gloria Brunori,
  • Shikha Singh,
  • KV Nageswar,
  • Haiyong Peng,
  • Christoph Rader,
  • Jérôme AJ Becker,
  • Julie Le Merrer,
  • Appu K. Singh,
  • Kirill A. Martemyanov

摘要

Development of therapies for neuropsychiatric conditions is one of the greatest challenges of modern medicine. Common limitations of traditional small molecule drugs include poor efficacy, off-target side effects and difficult druggability of many targets. In this study, we report a different approach deploying small engineered single domain antibodies, known as nanobodies, for the treatment of depression, a prevalent neuropsychiatric condition. We develop highly selective nanobodies for a recently discovered glycine receptor mGlyR crucially linked to pathophysiology of depression. Using a mouse model of stress-induced depression, we show that non-invasive intranasal delivery of nanobody produces rapid and lasting anti-depressant effect. We solve an atomic structure of mGlyR bound to nanobody and use a variety of cell-based approaches to reveal the mechanism of mGlyR modulation and its impact on neural circuitry. These findings support development of biologics for the treatment of intractable brain disorders.