Modifying brain molecule relaxin-3 can potentially reduce side effects in treating anxiety, depression and more

A team of researchers has discovered a possible way to treat these conditions with fewer side effects. Led by Professor Gavin Dew, head of the Department of Pharmacology at the Yong Lo Lin School of Medicine, National University of Singapore (NUS Medicine), the team modified relaxin-3 – a neuropeptide, or molecule, found primarily in the body. Is. The human brain and nervous system – which regulates a wide range of bodily functions, including stress responses, appetite, mood and pain perception. When relaxin-3 is released in the brain, it binds to a target receptor, RXFP3 — to trigger a variety of signaling responses between cells, which affect the body’s physiological processes.

However, as RXFP3 is involved in many different functions, a drug designed to treat specific conditions may cause unwanted side effects — because several RXFP3 signaling pathways are activated at the same time. For example, a drug that treats depression may cause negative effects related to another function, such as feeding behavior, which is associated with eating disorders and obesity. The receptor has also been shown in much current research, including earlier work by Professor Dew, to be a potential new target for drugs to treat these conditions. To develop better drug treatments with fewer side effects, the key is to activate specific RXFP3 signaling pathways that target specific conditions.

Professor Dawe’s team modified the relaxin-3 molecules, such that they activated only part of the RXFP3 response in their interaction, rather than all the different signaling pathways. His work, published in Science Signalingthis is the first finding that modulation of relaxin-3 can lead to selective activation of certain RXFP3-led signaling pathways, a mechanism known as biased agonism.

“Our studies point to possible ways to develop drugs by modifying relaxin-3, or other neuropeptides, that can selectively stimulate specific functions within the body. And less unwanted ones,” said Professor Dawe. negative effects, making them more effective in managing conditions such as anxiety, depression, eating disorders, obesity and addiction.”

Through a technique known as peptide stapling, the research team modified the B chain of relaxin-3, replacing blocks of amino acids within them with synthetic ones that introduce ‘chemical bridges’ between them. Alone, the B-chain is highly flexible and can bend and twist into many different conformations, reducing its ability to stabilize the receptor for more efficient binding and activation of RXFP3. The stapling process locks in specific B chain motifs in relaxin-3, stabilizing it for more efficient interaction with the RXFP3 receptor, where it activates specific signaling pathways in the brain that regulate physiological functions. affect

“We are at a very early stage in the journey to develop clinically useful drugs. However, our study shows promising results,” said first author of the study and former PhD student in NUS Medicine’s Department of Pharmacology. The results are in. An important step in our quest to design isolated stapled peptides that have selective effects on anxiety, depression, eating disorders and addiction. Our collaboration will seek to understand how proteins such as RXFP3 How biased agonists work at the molecular level.” She is leading a team of researchers working to understand the molecular properties of proteins such as RXFP3 at the Department of Chemistry, Faculty of Science, University of Colombo, Sri Lanka. are, where he is a lecturer in biochemistry and molecular biology.

With the conclusion of the study, the research team plans to use different stapled peptides to understand how the signaling functions triggered by the interactions between relaxin-3 and RXFP3 affect the body’s physiological functions and human behavior.