From spider venom to potential medical therapies.

Spider venom isn’t usually something people run towards. It is, after all, a toxin that can be anything from annoying to deadly.

But that’s not the case for researchers at The Wistar Institute, who have made a synthetic version of this naturally occurring compound, and used the same mechanism through which spiders paralyze insects to stop neurotransmitters in human brains from building up and becoming toxic. While the work, published in Molecular Pharmacology, is in early stages, it could lead to new medications to treat conditions like stroke, neuropathic pain and substance use disorders.

“Spider venom itself doesn’t make a very good drug. You can’t make a pill out of it,” said Joseph Salvino, Ph.D., medicinal chemist and professor in the Molecular & Cellular Oncogenesis Program and scientific director of the Molecular Screening & Protein Expression Facility at The Wistar Institute. “But medicinal chemists like myself are trying to convert it into something stable that could become a drug that changes lives.”

This research started in Brazil, where Andréia C.K. Mortensen, Ph.D., now an assistant professor in pharmacology and physiology at Drexel University College of Medicine, was a student at the University of São Paulo, Ribeirão Preto School of Medicine. There, she uncovered the biological component of how the spider venom Parawixia bistriata works. It’s not very toxic, but it uses the amino acid glutamate to disrupt an insect’s neuromuscular signals, which paralyzes them.

In humans, glutamate is an important neurotransmitter, but “if you get too much of it, you burn out the neuron and it becomes excitotoxic,” said Salvino. In this condition, neurons become stimulated constantly, which can lead to the development of neuropathic pain, epilepsy, stroke, and also potentially conditions like Alzheimer’s Disease. Glutamate signaling pathways are also altered through substance abuse disorder, which can exacerbate the condition.

“The compounds stimulate a glutamate transporter, called EAAT2, like a vacuum cleaner,” he said. “It just clears out the system and any nonsense going on.”

While the venom component from Parawixia bistriata itself isn’t a potential medical treatment, Salvino is exploring how a synthetic mimic of it could become one. His lab does that by making a lot of different compounds—each with their own unique properties—to see what might work. “What if we make it big? What if we make it small? What if we make it greasy?” he said. “Then we test it for its biological activity and ability to stimulate or inhibit activity.”

They’re looking not just at improving potency but also giving these naturally occurring compounds drug-like characteristics so that “ultimately we’re going to have a molecule that’s going to be potent and metabolically stable,” he said.

This kind of research is happening at Wistar because of Salvino, who is the Institute’s first medicinal chemist. He has spent more than 30 years working in drug discovery, first for pharmaceutical companies then in academia. In this role at The Wistar Institute, he collaborates with researchers across the organization on small molecule compounds to see how their findings might be translated into medical treatments for people.

“We’re taking natural products that aren’t very good drugs and turning them into something much more drug-like,” he said.

He’s also working on other projects, including creating potential drug treatments for Kaposi’s sarcoma, leukemia and other cancers, plus compounds to improve efficacy and safety of existing drugs.

While work with spider-venom based compounds is in the very early stages, with possible human uses years or even decades away, the potential is huge for neurological conditions and problems that would be improved by removing excess glutamate, like neuropathic pain, epilepsy, and stroke.

It could also be used to clear away glutamate related damage from conditions like Alzheimer’s Disease, become a treatment administered after a traumatic head injury to protect brain cells from the influx of glutamate that happens after such a trauma, or to interrupt the reward seeking behaviors that happen neurologically in people with substance use disorders.

“We’re trying to develop a drug to restore balance,” he said. “If you remove all the glutamate, it affects memory, but too much is going to be toxic. Figuring out the right amount and balance is going to be key to try to translate this into a therapeutic.”