During the pandemic, doctors are using transfused monoclonal antibodies (laboratory-produced antibodies) to help patients fight COVID-19 infection. Now UC Davis researchers are trying to create monoclonal antibodies that could help fight chronic pain. The goal is to develop a non-addictive monthly pain reliever that could replace opioids.
The project is led by Vladimir Yarov-Yarovoi and James Trimmer, professors in the Department of Physiology and Biology of Membrane at the University of California, Davis School of Medicine. They assembled a multidisciplinary team that included many of the same researchers who were trying to turn tarantula venom into painkillers.
Earlier this year, Yarov-Yarovoy and Trimmer received a $1.5 million grant from the National Institutes of Health’s HEAL program, which is an aggressive attempt to accelerate scientific solutions to contain the country’s opioid crisis.
Due to chronic pain, people can become addicted to opioids. The Centers for Disease Control’s National Center for Health Statistics estimates that there will be 107,622 drug overdose deaths in the United States in 2021, nearly 15% more than the estimated 93,655 deaths in 2020.
“Recent breakthroughs in structural and computational biology — the use of computers to understand and model biological systems — have laid the foundation for the application of new methods for creating antibodies as excellent drug candidates for treating chronic pain,” Yarov said. Yarovoy, the main performer of the Sai award.
“Monoclonal antibodies are the fastest growing area of the pharmaceutical industry and offer many advantages over classic small molecule drugs,” said Trimmer. Small molecule drugs are drugs that easily penetrate cells. They are widely used in medicine.
Over the years, Trimmer’s lab has created thousands of different monoclonal antibodies for a variety of purposes, but this is the first attempt to create an antibody designed to relieve pain.
Although it looks futuristic, the US Food and Drug Administration has approved monoclonal antibodies for the treatment and prevention of migraine. The new drugs act on a protein associated with migraine called the calcitonin gene-related peptide.
The UC Davis project has a different goal – specific ion channels in nerve cells called voltage-gated sodium channels. These channels are like “pores” on nerve cells.
“Nerve cells are responsible for transmitting pain signals in the body. Potential-gated sodium ion channels in nerve cells are key transmitters of pain,” explains Yarov-Yarovoy. “Our goal is to create antibodies that bind to these specific transmission sites at the molecular level, inhibit their activity and block the transmission of pain signals.”
The researchers focused on three specific sodium channels associated with pain: NaV1.7, NaV1.8, and NaV1.9.
Their goal is to create antibodies that match these channels, like a key that unlocks a lock. This targeted approach is designed to block the transmission of pain signals through the channel without interfering with other signals transmitted through nerve cells.
The problem is that the structure of the three channels they are trying to block is very complex.
To solve this problem, they turn to the Rosetta and AlphaFold programs. With Rosetta, researchers are developing complex virtual protein models and analyzing which models are best suited for the NaV1.7, NaV1.8, and NaV1.9 neural channels. With AlphaFold, researchers can independently test proteins developed by Rosetta.
Once they identified a few promising proteins, they created antibodies that could then be tested on neural tissue created in the lab. Human trials will take years.
But researchers are excited about the potential of this new approach. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and acetaminophen, must be taken several times a day to relieve pain. Opioid painkillers are usually taken daily and carry a risk of addiction.
However, monoclonal antibodies can circulate in the blood for more than a month before they are eventually broken down by the body. The researchers expected patients to self-administer the analgesic monoclonal antibody once a month.
“For patients with chronic pain, this is exactly what you need,” said Yarov-Yarovoy. “They experience pain not for days, but for weeks and months. It is expected that circulating antibodies will be able to provide pain relief that lasts for several weeks.”
Other team members include EPFL’s Bruno Correia, Yale’s Steven Waxman, EicOsis’ William Schmidt and Heike Wolf, Bruce Hammock, Teanne Griffith, Karen Wagner, John T. Sack, David J. Copenhaver, Scott Fishman, Daniel J. Tancredi, Hai Nguyen, Phuong Tran Nguyen, Diego Lopez Mateos, and Robert Stewart of UC Davis.
Out of business hours, holidays and weekends: hs-publicaffairs@ucdavis.edu916-734-2011 (ask a public relations officer)
Post time: Sep-29-2022