Reducing drug side effects in treating anxiety, depression


Drugs that treat conditions like depression and anxiety often come with varying side effects, as they regulate various functions within the human body at the same time. What if these drugs could activate only the functions that target the specific conditions that they are designed to treat?

A team of researchers has found a potential way to treat these conditions with fewer side effects. The team conducted modifications of relaxin-3—a neuropeptide, or molecule, found mainly in the human brain and nervous system—which regulates a wide range of physiological 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 signalling responses among the cells, which affect the body’s physiological processes.

However, as RXFP3 is involved in many different functions, a drug developed to treat certain conditions may cause unwanted side effects—because several of RXFP3’s signalling pathways are activated at the same time. For example, a drug that treats depression may cause adverse effects related to another function, such as feeding behaviour, which is related to eating disorders and obesity. The receptor has also been demonstrated in much existing research 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 only specific signalling pathways of RXFP3 that target specific conditions.

The team modified the relaxin-3 molecules, such that they activated only a part of the RXFP3 response in their interaction, instead of all the different signalling pathways. Their work, published in Science Signaling, is the first discovery that modifications of relaxin-3 can lead to selective activation of some RXFP3-led signalling pathways, which is a mechanism known as biased agonism.

The senior author said, “Our study has pointed to potential ways of developing drugs by modifying relaxin-3, or other neuropeptides, that can selectively activate specific functions within the body. This is important as it means drugs could be designed to have more specific effects and less undesired, adverse effects, making them more effective in managing a range of conditions like 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 artificial ones that introduce ‘chemical bridges’ between them. Alone, the B-chain is highly flexible and can twist and bend into many different shapes, reducing its ability to be stabilised for more effective binding and activation of the receptor RXFP3. The stapling process locks the shape of the specific B-chain in relaxin-3, stabilising it for a more efficient interaction with the receptor RXFP3, where it triggers certain signalling pathways in the brain that affect the body’s physiological functions.

The  first author of the study said, “We are at very early stages in terms of the journey in making clinically useful drugs. However, the promising findings from our study are a significant step in our aspiration to separately design stapled peptides that have selective effects on anxiety, depression, eating disorders and addiction. Our collaborative work would also strive to understand how proteins like RXFP3 function at a molecular level, with the help of biased agonists.”

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

https://www.science.org/doi/10.1126/scisignal.abl5880

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmechanisms-of-biased&filter=22

Rating

Unrated
Rating: