Disrupting GPCR Complexes with Smart Drug-like Peptides

Abstract

G protein-coupled receptors (GPCRs) are a superfamily of proteins classically described as monomeric transmembrane (TM) receptors. However, increasing evidence indicates that many GPCRs form higher-order assemblies made up of monomers pertaining to identical (homo) or to various (hetero) receptors. The formation and structure of these oligomers, their physiological role and possible therapeutic applications raise a variety of issues that are currently being actively explored. In this context, synthetic peptides derived from TM domains stand out as powerful tools that can be predictably targeted to disrupt GPCR oligomers, especially at the interface level, eventually impairing their action. However, despite such potential, TM-derived, GPCR-disrupting peptides often suffer from inadequate pharmacokinetic properties, such as low bioavailability, a short half-life or rapid clearance, which put into question their therapeutic relevance and promise. In this review, we provide a comprehensive overview of GPCR complexes, with an emphasis on current studies using GPCR-disrupting peptides mimicking TM domains involved in multimerization, and we also highlight recent strategies used to achieve drug-like versions of such TM peptide candidates for therapeutic application.

Oligomerization of the heteromeric γ-aminobutyric acid receptor GABAB in a eukaryotic cell-free system

“…Due to their nowadays widely accepted oligomerization, the knowledge of monomeric GPCRs as a functional entity has been turned upside down, and the alternated mechanisms, functionality, and role of oligomers in health need to be viewed and questioned in a detached manner 2 . This opens new perspectives on functional protein complexes, their medical role and intervention 35 . However, the lack of knowledge regarding protein-protein interactions and oligomerization of some GPCR is partially linked to challenges in heterologous expression and the requirement of a suitable surrounding environment to introduce protein assembly.…”

“…Accordingly, the BRET results reinforce the PLA finding and demonstrate a heterodimeric assembly of GABA B in the CFPS system . As drugs targeting the interaction of GABA B heterodimers have rarely been found, cell-free synthesized GABA B could be used for initial screens targeting neurological and psychiatric disorders by antagonists, such as small peptides 35 similar to the antinociceptive bivalent ligand targeting the heteromeric mGlu5-µ-opioid GPCR 54 .…”

Unraveling the crosstalk between renin‐angiotensin system receptors

“…Drug that can either enhance or disrupt receptor dimerization is another pharmacological strategy to target receptor heteromers. 98 Synthetic peptides derived from transmembrane domains emerge as potent tools that can be precisely targeted to disrupt or increase GPCRs F I G U R E 6 Pharmacological approaches to target receptor heteromers. (A) Bivalent ligands are drug molecules consisting of two ligands, each selective for one protomer and linked together by a spacer of defined length.…”

Evolving Experimental Techniques for Structure-Based Drug Design

“…Using this approach, the R g of the EGFR monomer was found to be ∼27 Å and the R g of the EGFR dimer was ∼39 Å, demonstrating a simple and direct readout for EGFR dimerization. In addition to detecting oligomerization, SAXS can also be employed to investigate protein–protein interactions that play an important role in human disease. − For example, C-terminal peptide fragments of G alpha subunits have been used to modulate GPCR signaling by competing with the native G-proteins and blocking GPCR signaling. , This presents an opportunity for using SAXS as a high-throughput approach for screening peptides for the disruption of GPCR/G-protein complexes.…”