title: GPCR-targeting nanobodies: attractive research tools, diagnostics, and therapeutics.
abstract: G-protein-coupled receptors (GPCRs) represent a major therapeutic target class. A large proportion of marketed drugs exert their effect through modulation of GPCR function, and GPCRs have been successfully targeted with small molecules. Yet, the number of small new molecular entities targeting GPCRs that has been approved as therapeutics in the past decade has been limited. With new and improved immunization-related technologies and advances in GPCR purification and expression techniques, antibody-based targeting of GPCRs has gained attention. The serendipitous discovery of a unique class of heavy chain antibodies (hcAbs) in the sera of camelids may provide novel GPCR-directed therapies. Antigen-binding fragments of hcAbs, also referred to as nanobodies, combine the advantages of both small molecules (e.g., molecular cavity binding, low production costs) and monoclonal antibodies (e.g., high affinity and specificity). Nanobodies are gaining ground as therapeutics and are also starting to find application as diagnostics and as high-quality tools in GPCR research. Herein, we review recent advances in the use of nanobodies in GPCR research.
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, de Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Azra
authors.initials: A
authors.lastname: Mujić-Delić
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, de Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Raymond H
authors.initials: RH
authors.lastname: de Wit
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, de Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.affiliation: Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, de Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. Electronic address: mj.smit@vu.nl.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Smit
mesh_terms: D000818:Animals; D006801:Humans; D058990:Molecular Targeted Therapy; D043562:Receptors, G-Protein-Coupled / Q000276:immunology* / Q000378:metabolism; D061905:Single-Domain Antibodies / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism
chemical_list: D043562:Receptors, G-Protein-Coupled; D061905:Single-Domain Antibodies
keywords: GPCRs; VHH; nanobodies; signaling; single-domain antibody