Martine Smit, PhD, Professor, Target and Systems Biochemistry, Medicinal Chemistry, Vrije University, The Netherlands
G protein-coupled receptors (GPCRs) represent a major therapeutic target class as they play a key role in many (patho)physiological processes. Besides small molecules, GPCRs can be effectively targeted by biologics. In particular, antibody fragments from camelid-derived heavy chain-only antibodies (nanobodies/VHHs) are attractive tools in detecting, stabilizing, modulating and therapeutically targeting GPCRs. The small size and molecular structure of nanobodies allow extracellular and intracellular modulation of GPCR function. Besides modulating GPCR activity as monovalent or multivalent constructs, nanobodies can also be functionalized for imaging and therapy. Examples of nanobodies targeting human and viral chemokine receptors will be provided. Moreover, GPCR-binding nanobodies have been instrumental in obtaining crystal structures of GPCRs, facilitating structure-based drug discovery. Thus, nanobodies are an important class of biologics targeting GPCRs.