GPCR ligand–dendrimer (GLiDe) conjugates: future smart drugs?

Unlike nanocarriers that are intended to release their drug cargo at the site of action, biocompatibile polyamidoamine (PAMAM) conjugates are designed to act at cell surface G protein-coupled receptors (GPCRs) without drug release. These multivalent GPCR ligand–dendrimer (GLiDe) conjugates display qualitatively different pharmacological properties in comparison with monomeric drugs. They might be useful as novel tools to study GPCR homodimers and heterodimers as well as higher aggregates. The structure of the conjugate determines the profile of biological activity, receptor selectivity, and physical properties such as water solubility. Prosthetic groups for characterization and imaging of receptors can be introduced without loss of affinity. The feasibility of targeting multiple adenosine and P2Y receptors for synergistic effects has been shown. Testing in vivo will be needed to explore the effects on pharmacokinetics and tissue targeting.