To address the unmet need for the treatment of moderate to severe pain, devoid of serious side effects, this project aims at biased G protein signaling ligands of the µ-opioid receptor (MOR). This G protein-coupled receptor (GPCR) is targeted by opioids, which serve as the commonly used analgesics in pain therapy. However, upon activation of GPCRs on the extracellular side, several signaling pathways can be initiated intracellularly. Recent findings have now demonstrated that the undesired effects associated with opioid use are linked to β-arrestin-2 recruitment, which make MOR ligands
'biased' for the G protein pathway highly desirable. Until recently, no tools were available to steer the bias of developed GPCR ligands. Hence, the finding that Nanobodies are able to stabilize specific GPCR conformations, is considered to be a breakthrough discovery. Such Nanobodies, also called ‘Confobodies’ in this context, can be engaged in fragment-based drug discovery to find clinical candidates able to selectively activate GPCRs, herein MOR. In this project, the Confobody approach is complemented with the chemical modification of in-house opioid peptidomimetics. The resulting peptidomimetics
can serve as potential therapeutics, as such, but they can also serve as 'biased' ligands used in the immunization protocol deployed for
the discovery of Confobodies. Altogether, this project will culminate in MOR ligands with safer pharmacology, as compared to the clinically applied analgesics.
Effective start/end date1/11/1931/10/21

    Research areas

  • Peptidomimetics, drug design

    Flemish discipline codes

  • Organic chemical synthesis

ID: 47876709