Targeting mGlyR with nanobodies for depression
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.
Authors
- Gloria Brunori
- Kirill A. Martemyanov (ORCID: https://orcid.org/0000-0002-9925-7599)
- Christoph Rader
- Thibaut Laboute
- Haiyong Peng
- Appu K. Singh (ORCID: https://orcid.org/0000-0002-2685-4018)
- Shikha Singh
- Mansi Sharma
- KV Nageswar
- Stefano Zucca
- Omar K. Sial
Institutions
- Université de Tours (FR)
- University of Miami (US)
- Inserm (FR)
- Translational Health Science and Technology Institute (IN)
- University of Florida (US)
- Physiologie de la Reproduction et des Comportements (FR)
- Columbia University (US)
- Indian Institute of Technology Kanpur (IN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-26
- DOI
- https://doi.org/10.1038/s41467-026-68339-x
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Frederick National Laboratory for Cancer Research
- Department of Biotechnology, Ministry of Science and Technology, India
- Indian Council of Medical Research
- Council of Scientific and Industrial Research, India
- Institut National de la Santé et de la Recherche Médicale
- Ministry of Education, India
- Centre National de la Recherche Scientifique
- Servier
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
- National Institutes of Health
- National Cancer Institute