Protein Engineering for Chronic Pain

Pain often serves as a vital signal of danger and potential tissue damage: Touching a hot stove or breaking a bone requires an immediate reaction to protect us. Such acute pain lasts only until the stimulus is taken away or the underlying injury has healed.

But chronic pain is altogether different – it continues beyond what is considered an expected period of healing, which is usually up to 3 months. Chronic pain is a complex condition requiring sustained treatment, often over a period of years, and opioid medications are not recommended due to the risk of addiction, ineffectiveness, and other side effects. A few non-opioid medications are available, and complementary or integrative health approaches can help, but in general, people with chronic pain have limited options for meaningful, lasting pain relief.

That is why new, non-opioid approaches are welcome, say Vladimir Yarov-Yarovoy, Ph.D., and Heike Wulff, Ph.D., of the University of California, Davis. The two scientists lead a 20-person team using computational biology to engineer a tarantula venom into a new treatment for chronic pain. This basic and translational research is part of the Optimizing Non-Addictive Therapies to Treat Pain research program in the Helping to End Addiction Long-term^® Initiative, or NIH HEAL Initiative^®.

Addressing Chronic Pain

Chronic pain is prevalent, affecting 20% of Americans. Neuropathic pain is one type of chronic pain that can result from progressive nerve disease, which can happen with diabetes, chemotherapy, or sciatica. Neuropathic pain begins when nerves are damaged and don’t function normally, causing abnormal patterns of electrical activity. Our brains interpret these irregular signals as pain, even if there’s no painful stimulus and the original injury has healed. For that reason, neuropathic pain is hard to target – and hard to treat.

One target for blocking pain is a family of proteins called voltage-gated sodium, “Nav,” ion channels. Humans have nine different types of Nav channels that are present in the heart, skeletal muscle, and nerves. One version (Nav1.7) functions within sensory cells that detect painful stimuli. Nav1.7 serves as a pain “thermostat” to control how electrically active these cells are – which leads to how much pain we feel. If it doesn’t work right, problems arise.

Certain types of pain syndromes run in families, and by studying them, scientists are closing in on chronic pain. For example, the complete inability to feel pain is an extremely rare condition affecting only a few people worldwide – and it turns out these individuals have a malfunctioning version of Nav1.7. The opposite scenario also points to Nav1.7 as a culprit. People with erythromelalgia, a severe type of neuropathic pain that causes skin redness and intermittent burning sensation in the hands and feet, have an overactive version of Nav1.7.

In the quest to find hope for people with chronic neuropathic pain, Nav1.7 has become a beacon. Other NIH-supported researchers are targeting Nav1.7 using gene-editing technologies and with chemical decoys. And HEAL-funded scientists are also pursuing a range of other non-opioid therapies for chronic pain.

A tarantula spider sitting on top of a leaf — The research team is working with a peptide from venom of the Peruvian green velvet tarantula, because it contains a strong blocker of the Nav1.7 ion channel.

Precision Poisons

Another source for clues is the natural world. Biologists and chemists have teamed up over the past few decades to explore, and also mimic, nature’s medicine chest.

Nearly 200,000 species of wildlife use some type of venom to immobilize or kill prey by targeting ion channels. These molecules are cellular gateways that open themselves up in the presence of an abundance of ions (charged particles like sodium, calcium, or potassium). This change in voltage creates an electrical pulse and an action: like the beat of a heart, contraction of a muscle, or firing of a nerve. Small versions of proteins in venom, called peptides, gum up ion channels, preventing them from doing their biological jobs.

“Nature designed peptides in venom to paralyze prey quickly by “stinging” several channels at once – to effectively impair the function of the nervous system, stop muscle movement, and prevent the heart from beating,” explains Yarov-Yarovoy.

The research team has set their sights on a peptide from venom of the Peruvian green velvet tarantula, because it contains a strong blocker of the Nav1.7 ion channel. But the peptide as it’s found in nature isn’t useful as a drug for chronic pain, because it is unstable and affects other channels in addition to Nav1.7. It blocks other Nav channels throughout the body – in the heart, skeletal muscle, brain, and muscle, which could cause terrible side effects.

So researchers are changing the peptide into something more suitable: a peptide that targets Nav1.7 in nerves only. The timing was just right for this molecular engineering maneuver. That’s because other scientists had just recently pieced together a three-dimensional portrait of the Nav1.7 channel entwined with the tarantula venom peptide. Knowing this precise molecular arrangement allows researchers to optimize a peptide’s physical properties: for example, to make it attach tighter and more precisely, as well as to make it more physically stable so it could be given as a drug.

The team is now refining the design of the tarantula peptide using a computer software program called Rosetta. Just as the famous stone of the same name once helped linguists decipher ancient languages, Rosetta software uses information about a protein’s amino-acid sequence to predict all the possible shapes it can fold into. Researchers can then choose which ones fit their needs and are using this approach to design peptide-based treatments for conditions like cancer and COVID-19.

women experiencing chronic pain laying on couch — HEAL-funded researchers are working to develop non-opioid medications for chronic pain, which is pain that can last for weeks, months, or even years.

A Perfect Fit

Yarov-Yarovoy and Wulff are using Rosetta to custom-design versions of venom peptides that fit perfectly into the Nav1.7 channel. The process is efficient, since a computer can run millions of simulations to find peptides with specific shapes and desirable properties. The research team is also generating thousands of different versions of peptides that block Nav1.8 and Nav1.9, molecular cousins of Nav1.7, hoping to create a new class of non-opioid treatments for neuropathic pain.

The research team includes a range of expertise to design and refine the peptides, test their ability to block pain signals in cells and in animals, and offer advice about pain management in humans. For example, Yarov-Yarovoy’s University of California, Davis, colleague and team member David Copenhaver, M.D., M.P.H., routinely treats patients who suffer from chronic pain and sees significant unmet medical need for effective pain relief.

“Sometimes chemotherapy-induced neuropathic pain is so problematic that a patient won't continue chemo, which is a lifesaving treatment, because the pain is so severe,” Copenhaver explains.

Patients with other conditions are also desperate for better treatments, Copenhaver adds, like those suffering from shingles and other types of cancer-related pain from radiation and surgery. Individuals experiencing pain from injured or diseased discs in the spine also have limited options for safe and effective treatment.

Having lots of treatment options for chronic pain is important, since people experience it in many different ways – and they deserve choices of safe and effective medications that work for their unique circumstances. Like any long-term health problem, people with chronic pain often have other conditions, such as new or worsened depression, anxiety, difficulty sleeping, and substance use disorders.

Yarov-Yarovoy and Wulff’s team are at the beginning of this work, and they note that any new pain medicine is at least 5 years away. Molecules that look great in the lab and in animals need to be carefully tested in people, and that takes time.

But given the urgency of the chronic pain and opioid crises, the computer-driven process used in this research should be able to shave lots of time from the process of choosing the best peptides for treating chronic pain – and every minute is valuable for the millions of people who live with disabling pain.

Research Program:

Development and Optimization of Non-Addictive Therapies to Treat Pain

Research Focus Area:

Preclinical and Translational Research in Pain Management