Unlocking the Potential of Specific Drugs: A New Way to Activate G Protein-Coupled Receptors
Have you ever wondered how drugs reach their targets in the body and achieve their function? G protein-coupled receptors (GPCRs) are one such receptor that plays a role in the transmission of molecular signals and is involved in the activation of a third of existing drugs. However, adverse side effects can occur if drugs activate multiple signaling pathways, making drug development challenging. Activating the GPCR from inside the cell rather than outside the cell could be one way to achieve specificity. Until recently, there was no evidence of direct activation of only the intracellular side of the GPCRs without the initiations of the extracellular side.
New Research Shows a New Way to Activate G Protein-Coupled Receptors (GPCRs)
A team of Japanese researchers led by Osamu Nureki, a professor at the University of Tokyo, discovered a new mode of receptor activation of a GPCR related to bone metabolism, called human parathyroid hormone receptor type 1 (PTH1R), without transduction of signal from the extracellular side. They used cryoelectron microscopy to reveal the 3D structure of the PTH1R and G protein bound to a messenger molecule, synthesized a non-peptide messenger molecule called PCO371 that binds to the intracellular region of the receptor, and directly interacts with G protein subunits.
Drug Development Takes a New Turn with PCO371
The PCO371-bound PTH1R structure directly and stably modulates the intracellular side of PTH1R. It activates only G protein and not ß-arrestin, leading to drug candidates that currently lack orally administered drug ligands. Such drugs would have reduced adverse effects and burdens for patients, acting on specific molecular pathways. This specificity of activation could result in appropriate medications for disorders such as obesity, pain, osteoporosis, and neurological disorders, that currently require strict dosing and have administrative restrictions, with no alternative yet.
More to Come in the Field of G Protein-Coupled Receptors (GPCRs)
The findings of this study open new doors to further research focused on specific molecular pathways within cells, making drug development easier. Furthermore, the drug presents a promising treatment for osteoporosis, and its understanding of the molecular mechanism allows for optimal drug design.
Summary:
Japanese researchers have discovered a new way to activate G protein-coupled receptors (GPCRs) by triggering shape changes in the intracellular side of the receptor. Activating the GPCR from inside the cell instead of outside the cell could be one way to achieve specificity and design drugs with fewer or no side effects. Calls for developing new drugs for disorders such as obesity, pain, osteoporosis, and neurological disorders have been made possible by these recent findings. The non-peptide messenger molecule called PCO371, which accelerates the activation of specific molecular pathways through GPCRs, offers a promising treatment for osteoporosis.
GPCRs activations could revolutionize drug development. Furthermore, the new mode of receptor activation of PTH1R could result in more orally administered medications for specific molecular pathways that presently require strict dosing and have administrative restrictions.
Additional Piece:
The new mode of receptor activation has opened a new field in drug development, which has been a continuous challenge in the medical industry. Advances in science and research are continuously made every single day, and in recent years, there has been a promising increase in the development of new drugs. However, drugs that have previously been created have come with side effects that hurt patients in several ways. This new approach could work as a foundation for creating more medications that avoid the present health risks related to drug administration.
According to the Centre for Disease Control (CDC), over 40% of Americans utilize prescription drugs. Unfortunately, recent studies have shown that there has been an increase in drug abuse as well as conventional hardships in administering medication with increasing age. This makes the development of medications that reduce dosage frequency and administration requirements, thanks to a new mode of receptor activation, incredibly important.
Moving Forward
The findings of this study open new doors to more research focused on specific elements of drug administration and ways to minimize adverse side effects while maximizing comfort in medication administration. More can be done in the field of G protein-coupled receptors (GPCRs), resulting in a wider variety of accessible medication for individuals globally.
Conclusion
The discovery of a new way to activate G protein-coupled receptors (GPCRs) has created a vast array of possibilities for creating newer, safer medications. The non-peptide messenger molecule called PCO371, which accelerates the activation of specific molecular pathways through GPCRs, offers a promising way of treating previously unaddressed disorders such as obesity, pain, osteoporosis, and neurological disorders. With research results indicating a decreased likelihood of side effects in medication, there is a hopeful prospect ahead of us. The future we envision involves the creation of newer medications that are safer, work more effectively, and result in an improved quality of life for people globally.
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Have you ever wondered how drugs reach their targets and achieve their function within our body? If a drug molecule or a ligand is a message, an inbox is usually a receptor on the cell membrane. One such receptor involved in the transmission of molecular signals is a G protein-coupled receptor (GPCR). About a third of existing drugs work by controlling the activation of this protein. Japanese researchers now reveal a new way to activate GPCR by triggering shape changes in the intracellular region of the receptor. This new process may help researchers design drugs with fewer or no side effects.
If the cell membrane is like an Oreo cookie sandwich, GPCR is like a snake with seven segments running through the surface of the cookie sandwich. The extracellular loops are the message inbox. When a messenger molecule binds to the extracellular side of the receptor, it triggers a shape change that activates G proteins and the ß-arrestin protein bound to the intracellular side of the receptor. Like a molecular relay, information passes downstream and affects various bodily processes. This is how we see, smell and taste, which are sensations of messages of light, smell and taste.
Adverse side effects occur if drugs that act on GPCRs activate multiple signaling pathways instead of a specific target pathway. That is why drug development focuses on activating specific molecular signaling pathways within cells. Activating the GPCR from inside the cell instead of outside the cell could be one way to achieve specificity. But until now, there was no evidence of direct activation of only the intracellular side of the GPCRs without the initiations of the extracellular side.
A team of researchers led by Osamu Nureki, a professor at the University of Tokyo, and his laboratory discovered a new mode of receptor activation of a GPCR related to bone metabolism called human parathyroid hormone receptor type 1 (PTH1R) without transduction of signal from the extracellular side.
“Understanding the molecular mechanism will allow us to design optimal drugs,” says Kazuhiro Kobayashi, a doctoral student and author of the study. Such a drug offers “a promising treatment for osteoporosis.”
Kobayashi has been conducting research on bone formation in animal models since he was a college student. “Osteoporosis treatments that target PTH1R require strict dosing, have administrative restrictions, and there are no better alternatives yet,” he says. That motivated his team to look for better drug design strategies targeting the parathyroid hormone receptor.
To understand function through structure, they used cryoelectron microscopy and revealed the 3D structure of the PTH1R and G protein bound to a messenger molecule. The team synthesized a non-peptide messenger molecule called PCO371 that binds to the intracellular region of the receptor and directly interacts 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 doesn’t cause side effects. This specificity of its mode of receptor binding and activation makes it a suitable candidate for potential small molecule-based drugs for class B1 GPCRs, such as PTH1R, which currently lack orally administered drug ligands. Such drugs would have reduced adverse effects and burdens for patients, since they act on specific molecular pathways.
The findings of this study will help “develop new drugs for disorders such as obesity, pain, osteoporosis, and neurological disorders.”
The study appears in the journal Nature.
https://www.sciencedaily.com/releases/2023/06/230608121022.htm
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