Researchers from the Institute for Research in Biomedicine in Barcelona, Spain said yesterday that they have shown in preclinical tests that a bee-venom peptide, apamin, can be used to ferry medications across the blood-brain barrier.
Although the blood-brain barrier prevents most things from getting in and flooding the brain, certain peptides in animal venoms can travel across the membrane and inflict damage. The researchers though that that they could take advantage of this function to help deliver medicines directly to the brain.
“We thought that because the venoms of some animals are able to attack the central nervous system, they should be able to go through the blood-brain barrier and possibly shuttle drugs across it,” principal investigator Ernest Giralt said in prepared remarks. “We knew we could not use apamin directly because it’s toxic. But the good news is that the origin of the toxicity is well-known. We thought we could probably modify apamin in such a way that the toxicity would be eliminated, but it would still keep its ability to act as a transporter.”
Apamin is toxic thanks to a positively-charged group in the molecule that mimics potassium ions, which blocks the potassium channel in neurons. To rid apamin of its toxicity, the researchers removed the positively-charged chemical group that helps bind apamin to the channel.
“This modification made apamin much less toxic, and its ability to cross the BBB was intact,” Giralt said. “This was very good news.”
Then the team made the molecule smaller so as to reduce the possibility of detection by the body’s immune system. Eventually, they ended up with a version of apamin that the team referred to as “Mini-Ap4”.
“It surprised us that this molecule crossed the blood-brain barrier much better than apamin itself – it was pure serendipity,” Giralt said. The small molecule also did not set off a strong immune system response in animal models, the team said.
Other molecules that shuttle drugs across the blood-brain barrier are in development, but they are largely based on linear peptides, which the researchers said are degraded by proteases before the drug even makes it to the brain.
“Our niche is that our peptides are cyclic, or in a ring structure, making them completely resistant to proteases,” Giralt explained.
After the initial preclinical studies, the team plans to attach Mini-Ap4 to a protein and see if can can ferry cargo across the blood-brain barrier. They will also try filling a nanoparticle with drugs and coating it with Mini-Ap4 molecules to get across the barrier in human cells and mice, the researchers reported.