Modulating GPCR signaling through development of β-arrestin peptidomimetics

G protein-coupled receptors (GPCRs) are an important family of membrane receptors that play a
central role in modern medicine. Their signaling represents a complex process involving both G
protein- and arrestin-dependent pathways. However, the molecular bases and functional
consequences of this signaling pleiotropy mostly remain to be elucidated and this requires innovative
pharmacological tools that would selectively affect each of these pathways. Although such tools are
emerging for G protein signaling, this is not the case for arrestin-dependent pathways. Therefore, we
aim to mimic β-arrestin by means of peptidomimetics, using a structure-based design strategy.
Interestingly, the finger loop in the central crest of the GPCR-binding site of β-arrestin has been
identified as key epitope. Hence, peptidomimetics based on this finger loop template are envisioned
and these will be screened by a radioligand displacement assay to identify peptides able to bind and
stabilize GPCRs in an active conformation. Through use of a case study on the ghrelin receptor, the
best-performing peptidomimetics will be deployed to investigate β-arrestin-linked intracellular
signaling pathways by conjugating cell-penetrating peptides. These allosteric peptidomimetics will
permit the identification of novel orthosteric compounds, selective for arrestin-dependent pathways,
and illuminate structural and mechanistic aspects of GPCR-β-arrestin interactions and the resulting
functional outcomes