Groundbreaking Approach to Drug Development May Eliminate Side Effects

An illustrative depiction of the activation of the GPCR from within the cell, leading to a targeted reaction. Credit: Kobayashi and Kawakami et al., 2023

A novel method of activating G-protein coupled receptors (GPCRs) from within cells has been unveiled by researchers, paving the way for the creation of drugs without side effects.

Ever considered how medications manage to reach their designated targets and function within our bodies? Picture the drug molecule or ligand as a dispatch, and the cell membrane receptor as the postbox. One such postman, delivering molecular signals, is the G-protein coupled receptor (GPCR).

Notably, about one-third of all drugs on the market function by manipulating the activation of this protein. A team of Japanese scientists has now uncovered a fresh way of activating the GPCR by instigating shape alterations in the receptor’s intracellular region. This innovative process can aid in designing medications with reduced or zero side effects.

The cell membrane can be likened to an Oreo cookie, with the GPCR being analogous to a snake threading through the cookie’s surface in seven segments. The outer loops act as the postbox for messages. When a message molecule binds to the outer side of the receptor, it initiates a shape transformation, activating G proteins and the ß-arrestin protein attached to the inner side of the receptor. Like a molecular baton pass, the information travels downstream, affecting a range of bodily functions. This is how we experience senses such as sight, smell, and taste.

Unwanted side effects can occur if drugs targeting GPCRs stimulate multiple signaling pathways instead of a specific target pathway. Therefore, drug development emphasizes activating specific molecular signal pathways within cells. Stimulating the GPCR from within the cell, not from outside, may be a means to achieve this specificity. However, until now, there was no known method of activating only the intracellular side of GPCRs without initiating signals from the extracellular side.

Headed by Professor Osamu Nureki from the University of Tokyo, a group of researchers discovered a new mode of receptor activation for a bone metabolism-related GPCR named human parathyroid hormone type 1 receptor (PTH1R) without signal transduction from the extracellular side.

“Deciphering the molecular mechanism will empower us to develop optimal drugs,” comments Kazuhiro Kobayashi, a Ph.D. student and a co-author of the study, who sees potential in this discovery for improved osteoporosis treatments.

Kobayashi, who has been researching bone formation in animal models since his undergraduate years, notes the current treatment limitations for osteoporosis targeting PTH1R. “There is a need for strict dosage control, administration restrictions exist, and better alternatives are not yet available,” he observes. This spurred the team to explore improved drug design strategies targeting the parathyroid hormone receptor.

The researchers used cryo-electron microscopy to reveal the 3D structure of PTH1R and G protein bound to a message molecule. They synthesized a non-peptide message molecule called PCO371, which binds to the intracellular region of the receptor and directly interacts with G protein subunits, essentially activating the receptor from inside the cell.

The structure of PTH1R when bound to PCO371 can directly and stably alter the receptor’s intracellular side. Since PCO371 only activates the G protein and not ß-arrestin, it avoids causing side effects. The specificity of its binding and mode of receptor activation makes it a potential candidate for future small-molecule-based drugs for class B1 GPCRs, like PTH1R, which currently have no orally administrable drug ligands. Such drugs could decrease negative effects and patient burdens by acting on specific molecular pathways.

The insights from this research are expected to “pave the way for new treatments for conditions such as obesity, pain, osteoporosis, and neurological disorders.”

Reference: “Class B1 GPCR activation by an intracellular agonist” by 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 and Osamu Nureki, 7 June 2023, Nature.
DOI: 10.1038/s41586-023-06169-3

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• G-protein coupled receptors (GPCRs)
• Introduction to Drug Development
• The Role of GPCRs in Drug Discovery
• Cryo-electron Microscopy
• Understanding Osteoporosis