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Novel Method to Activate G-protein Coupled Receptors for Drug Development without Side Effects
Introduction
Researchers have discovered a novel method to activate G-protein coupled receptors (GPCRs) from inside cells to develop drugs for treating conditions like obesity, pain, osteoporosis, and neurological disorders. The method involves identifying a specific molecule that can interact with the intracellular region of a GPCR. This approach can help researchers design drugs with fewer or no side effects.
The Function of GPCRs in Drug Development
One-third of existing drugs work by controlling the activation of G-protein coupled receptors (GPCRs), which function as messengers and relay molecular signals involved in relaying molecular signals. The receptor has seven different segments that traverse in and out of the cell membrane, with extracellular loops that serve as an inbox for messages. When a message molecule binds to the extracellular side of the receptor, it triggers a shape change activating G proteins and ß-arrestin protein attached to the intracellular side of the receptor. This molecular relay of information downstream affects various bodily processes like sight, smell, and taste. Adverse side effects ensue if drugs acting on GPCRs activate multiple signaling pathways rather than a specific target pathway.
The Study
A team of researchers headed by Osamu Nureki, a professor at the University of Tokyo, has 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.
The Findings
The team synthesized a non-peptide message molecule called PCO371 that binds to the intracellular region of the receptor and interacts directly with G protein subunits, thus activating it. PCO371 activates only G protein and not ß-arrestin, so it does not cause any 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.
Conclusion
Understanding how drugs target specific molecular signal pathways within cells can enable researchers to design optimal drugs with fewer or no side effects. The team has revealed a way to activate GPCR by triggering shape changes in the intracellular region of the receptor, which can help drug development and designing drugs with fewer or no side effects. The study will help develop new drugs for disorders such as obesity, pain, osteoporosis, and neurological disorders.
FAQ (Frequently Asked Questions)
What is GPCR?
G protein-coupled receptors (GPCRs) relay molecular signals involved in various bodily processes like sight, smell, and taste and help in drug development.
How can activating GPCR inside cells help drug development?
Activating GPCR from inside the cell rather than outside the cell could be one way to achieve specificity in drug development. This method can help researchers design drugs with fewer or no side effects.
What was the discovery made by the researchers?
Researchers have discovered a new way of activating the G protein-coupled receptor by triggering shape changes in the intracellular region of the receptor via a molecule called PCO371.
What are the benefits of PCO371?
Unlike other drugs that affect multiple signaling pathways, PCO371 activates only G protein and not ß-arrestin, so it does not cause any side effects. This helps in developing small-molecule-based drugs for specific molecular pathways.
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