The current research examines a novel method for the design of antibody-based drugs against G protein–coupled receptors (GPCRs), proteins involved in numerous physiological processes and often the targets of pharmacological intervention. GPCRs have traditionally been treated with small-molecule drugs; these, however, have the potential to produce unwanted side effects as a result of their lack of specificity. Although antibody-based drugs can potentially be a better option, their design for GPCR targeting is especially challenging as a result of the nature of these proteins.
The researchers developed a method to find tiny antibody fragments called “nanobodies” that can specifically target G-protein coupled receptors (GPCRs). They targeted the angiotensin II type I receptor (AT1R), a crucial target in hypertension and kidney disease treatment. Screening with a library of synthetic nanobodies, they identified and selected candidates to bind to AT1R in various manners—some as allosteric modulators (altering receptor function), and others as competitive inhibitors (inhibiting receptor function).
The study discovered that nanobodies are highly flexible, and their function can be altered. In particular, the researchers redesigned two nanobodies from allosteric modulators to competitive inhibitors by simple mutations. Therefore, it is implied that the nanobodies can be designed to modulate GPCR activity more selectively than traditional drugs.
The scientists also applied high-level imaging methods (cryo-electron microscopy) to investigate how the nanobodies interact with AT1R at the molecular level. This enabled them to determine the precise manner in which these molecules interact with and affect the function of the receptor.
In general, the research implies that nanobodies may represent a potent new method of designing drugs for GPCRs, especially for those cases where currently available small-molecule drugs are ineffective. This may lead to more targeted and efficient treatments for many diseases.
