Pharmacology of Viral GPCRs: All-Round Chemokine Receptor Homologs

Abstract

Herpesviruses are ubiquitous pathogens that are linked to severe pathologies such as proliferative, cardiovascular and post-transplant diseases. Several herpesviruses encode G protein-coupled receptors (GPCRs) with structural similarities to host chemokine receptors. These viral GPCRs play an important role in the viral life cycle and hijack cellular signaling pathways, potentially contributing to the herpesvirus-associated diseases and are therefore considered as attractive drug targets. In this review, we discuss the pharmacological, signaling and trafficking properties of viral GPCRs in a multitude of cellular and in vivo contexts. Elevated levels of constitutive activity and endocytosis, promiscuity in chemokine binding and G protein coupling, as well as their large propensity to oligomerize are features that can all be attributed to viral GPCRs. Additionally, the molecular basis for these unique signaling and trafficking signatures of viral GPCRs and means to pharmacologically modulate their function were described. At last, novel concepts in the field of GPCR pharmacology and signal transduction, such as biased signaling and location bias were addressed. Comparing viral GPCRs to their human homologs highlights the multifaceted and all-round nature of the viral receptors.