Caption: Activation of GPCR from inside the cell. (Image credit: Kobayashi and Kawakami et al., 2023)
Researchers have made a groundbreaking discovery in drug development that allows for the activation of G-protein coupled receptors (GPCRs) from inside cells, leading to the potential development of drugs with minimal side effects.
The research team has identified a molecule called PCO371, which interacts with the intracellular region of a specific GPCR. This finding offers a promising avenue for the treatment of conditions such as obesity, pain, osteoporosis, and neurological disorders.
Have you ever wondered how drugs precisely target their intended locations within our bodies? If drug molecules are messengers, the receptors on cell membranes can be thought of as inboxes. G protein-coupled receptors (GPCRs) are one type of receptor that plays a crucial role in transmitting molecular signals. In fact, about one-third of existing drugs work by controlling the activation of GPCRs. Japanese researchers have now unveiled a new method of activating GPCRs by inducing shape changes in the intracellular region of the receptor. This innovative process has the potential to facilitate the design of drugs with fewer or even no side effects.
If we liken the cell membrane to an Oreo cookie sandwich, GPCRs can be visualized as a snake with seven segments that traverse in and out of the cookie surface. The extracellular loops of GPCRs serve as the message inboxes. When a signaling molecule binds to the extracellular side of the receptor, it triggers a shape change that activates G proteins and ß-arrestin proteins attached to the intracellular side of the receptor. Like a molecular relay, this information is then transmitted downstream, influencing various physiological processes. This is how we perceive senses such as sight, smell, and taste, which are essentially interpretations of light, smell, and taste messages.
Caption: Resulting targeted response from GPCR activation inside the cell. (Image credit: Kobayashi and Kawakami et al., 2023)
Undesirable side effects occur when drugs that act on GPCRs activate multiple signaling pathways instead of just the desired target pathway. This is why drug development focuses on activating specific molecular signaling pathways within cells. Activating GPCRs from inside the cell, as opposed to the outside, could be a way to achieve greater specificity. However, until now, there had been no evidence of direct activation solely on the intracellular side of GPCRs, without initiation from the extracellular side.
A team of researchers led by Professor Osamu Nureki from the University of Tokyo has now discovered a new mode of receptor activation for a GPCR called the human parathyroid hormone type 1 receptor (PTH1R), which is involved in bone metabolism. Remarkably, this activation occurs without any signal transduction from the extracellular side.
According to Kazuhiro Kobayashi, a doctoral student and study co-author, understanding the molecular mechanism behind this discovery will enable the design of optimal drugs. He believes that such drugs hold great promise for the treatment of osteoporosis, a field he has been researching since his undergraduate years. Kobayashi notes that current osteoporosis treatments targeting PTH1R require strict dosage control, have limited administration routes, and lack superior alternatives. This motivated their team to explore improved drug design strategies aimed at the parathyroid hormone receptor.
To gain insight into the receptor’s function through its structure, the researchers employed cryo-electron microscopy to reveal the three-dimensional structure of PTH1R and the G protein bound to a signaling molecule. The team synthesized a non-peptide signaling molecule called PCO371, which binds to the intracellular region of the receptor and directly interacts with G protein subunits. In other words, PCO371 activates the receptor once it enters the cell.
The structure of PTH1R bound to PCO371 enables direct and stable modulation of the receptor’s intracellular side. Moreover, since PCO371 activates only G proteins and not ß-arrestin, it avoids causing side effects. This binding specificity and receptor activation mode make it a promising candidate for the development of small-molecule-based drugs targeting class B1 GPCRs like PTH1R, which currently lack orally administrable drug ligands. Such drugs would have reduced adverse effects and lessen the burden on patients, as they selectively act on specific molecular pathways.
The findings from this study have significant implications for the development of new drugs to treat disorders such as obesity, pain, osteoporosis, and neurological disorders.
The study has been published in the journal Nature.
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
Table of Contents
Frequently Asked Questions (FAQs) about Drug development
What is the significance of activating G-protein coupled receptors (GPCRs) from inside cells in drug development?
Activating GPCRs from inside cells is significant because it offers a way to develop drugs with reduced side effects. By triggering shape changes in the intracellular region of the receptor, researchers can achieve greater specificity in targeting specific molecular signal pathways within cells. This can lead to the design of drugs that act more selectively and minimize adverse effects.
What is PCO371 and how does it contribute to drug development?
PCO371 is a molecule that interacts with the intracellular region of a specific GPCR. It has been discovered to activate the receptor after entering the cell, thereby offering a novel approach to drug development. PCO371 directly interacts with G protein subunits, leading to receptor activation without triggering side effects associated with other pathways. Its binding specificity and activation mode make it a potential candidate for the development of small-molecule-based drugs with enhanced efficacy and reduced adverse effects.
Which conditions can potentially be treated using this new drug development approach?
The new drug development approach involving the activation of GPCRs from inside cells holds promise for treating various conditions. Some of these conditions include obesity, pain, osteoporosis, and neurological disorders. By targeting specific molecular pathways, drugs developed using this approach may offer improved treatments for these conditions, potentially with fewer side effects and better patient outcomes.
How does this research contribute to the future of drug design?
This research significantly contributes to the future of drug design by providing insights into activating GPCRs from inside cells. Understanding the molecular mechanisms involved enables the design of more optimal drugs. By targeting specific intracellular regions of GPCRs, researchers can aim for greater selectivity in drug action, reducing off-target effects and enhancing therapeutic outcomes. This research opens up new possibilities for developing safer and more effective drugs across various medical conditions.
Where was this research conducted, and where can I find more information?
This research was conducted by a team of researchers led by Professor Osamu Nureki at the University of Tokyo. The study has been published in the journal Nature. For more detailed information on the research methodology, findings, and implications, you can refer to the published paper titled “Class B1 GPCR activation by an intracellular agonist” by Kazuhiro Kobayashi et al. (DOI: 10.1038/s41586-023-06169-3).
