'Miracle Poison' For Novel Therapeutics
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When people hear botulinum toxin, they often think one of two things: a cosmetic that makes frown lines disappear or a deadly poison. But the miracle poison, as it's also known, has been approved by the F.D.A. to treat a suite of maladies like chronic migraines, uncontrolled blinking, and certain muscle spasms.

A team of researchers for the first time, proved they could rapidly evolve the toxin in the laboratory to target a variety of different proteins, creating a suite of bespoke, super-selective proteins called proteases with the potential to aid in neuroregeneration, regulate growth hormones, calm rampant inflammation, or dampen the life-threatening immune response called cytokine storm.

The team successfully reprogrammed proteases to cut entirely new protein targets. They also started to address called a "classical challenge in biology": designing treatments that can cross into a cell. Unlike most large proteins, botulinum toxin proteases can enter neurons in large numbers.

A lab invention called PACE rapidly evolves novel proteins with valuable features. PACE can evolve dozens of generations of proteins a day with minimal human intervention. The team first taught so-called "promiscuous" proteases to stop cutting certain targets. Then they taught a protease to only recognize an entirely new target.

With PACE, they evolved four proteases from three families of botulinum toxin; all four had no detected activity on their original targets and cut their new targets with a high level of specificity. The proteases also retained their valuable ability to enter cells. "You end up with a powerful tool to do intracellular therapy," said a researcher.

Still, since the immune system takes time to identify foreign substances, the proteases could be effective for temporary treatments. And, to side-step the immune response, the team is also looking to evolve other classes of mammalian proteases since the human body is less likely to attack proteins that resemble their own.

Source:
https://science.sciencemag.org/content/371/6531/803
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