Novel way to develop drugs without side effects

Japanese researchers now reveal a new way of activating GPCR by triggering shape changes in the intracellular region of the receptor. This new process can help researchers design drugs with fewer or no side effects.

Adverse side effects ensue if drugs acting on GPCRs activate multiple signaling pathways rather than a specific target pathway. That is why drug development focuses on activating specific molecular signal pathways within cells. Activating the GPCR from inside the cell rather than outside the cell could be one way to achieve specificity.

A team of researchers headed by Osamu Nureki, a professor at the University of Tokyo, and his lab, discovered a new receptor activation mode of a bone metabolism-related GPCR called human parathyroid hormone type 1 receptor (PTH1R) without signal transduction from the extracellular side.

To understand function through structure, they used cryo-electron microscopy and revealed the 3D structure of the PTH1R and G protein bound to a message molecule. The team synthesized a non-peptide message molecule called PCO371 which binds to the intracellular region of the receptor and interacts directly with G protein subunits. In other words, PCO371 activates the receptor after entering the cell.

The PCO371-bound PTH1R structure can directly and stably modulate the intracellular side of PTH1R. And because PCO371 activates only G protein and not ß-arrestin it does not cause side effects.

Reference:

Class B1 GPCR activation by an intracellular agonist,Nature,DOI 10.1038/s41586-023-06169-3