Are Drugs With Fewer or No Side Effects Possible?

Have you ever wondered how drugs reach their targets and achieve their function within our bodies? If a drug molecule or a ligand is a message, an inbox is typically a receptor in the cell membrane. One such receptor involved in relaying molecular signals is a G protein-coupled receptor (GPCR). About one-third of existing drugs work by controlling the activation of this protein. 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 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.

“Understanding the molecular mechanism will enable us to design optimal drugs,” says Kazuhiro Kobayashi, a doctoral student and an author of the study. 

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. This specificity of its binding and receptor activation mode makes it a suitable candidate for potential small-molecule-based drugs for class B1 GPCRs, like PTH1R, which currently lack oral administrative drug ligands. 

The findings from this study will help “develop new drugs for disorders such as obesity, pain, osteoporosis, and neurological disorders.”

Sources:

Kazuhiro Kobayashi, Kouki Kawakami, Tsukasa Kusakizako, Atsuhiro Tomita, Michihiro Nishimura, Kazuhiro Sawada, Hiroyuki H. Okamoto, Suzune Hiratsuka, Gaku Nakamura, Riku Kuwabara, Hiroshi Noda, Hiroyasu Muramatsu, Masaru Shimizu, Tomohiko Taguchi, Asuka Inoue, Takeshi Murata, Osamu Nureki. Class B1 GPCR activation by an intracellular agonist. Nature, 2023; DOI: 10.1038/s41586-023-06169-3

School of Science, The University of Tokyo. “A new way to develop drugs without side effects.” ScienceDaily. ScienceDaily, 8 June 2023. <www.sciencedaily.com/releases/2023/06/230608121022.htm>.

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