Scientists have created a high-speed method to generate thousands of small, stable proteins that can be designed to bind to specific therapeutic target.
The computer-designed proteins do not exist in nature and have the potential to become a new class of drugs that bridges the gap between small molecule drugs and biologics according to the study’s lead scientist David Baker. While the drugs have the stability and bioavailability of small molecule drugs, they also possess the specificity and potency of larger biologics.
The study was done by Baker and colleagues at the the University of Washington Institute for Protein Design and published this week in Nature.
Using a computer platform called Rosetta developed by Baker and colleagues, they designed thousands of short proteins, and ran them through the program to predict how tightly these would bind to their targets.
Due to their small size, the proteins tended to be extremely stable, able to be stored without refrigeration and more easily administered than large protein drugs. On the other hand, the fact that they are original designs allowed them to more tightly bind to their targets than other small molecule designs.
As proof of concept, the researchers sought to design two sets of proteins: one that would prevent influenza virus from invading cells by targeting H1 hemagglutinin and one to neutralize a deadly nerve toxin from botulism, botulinum neurotoxin B.
The computer modeling identified amino-acid sequences of thousands of short proteins for the targets. The researchers created short pieces of DNA that coded for these proteins, grew them in yeast cells, and looked at how tightly they bound to the targets.
After narrowing down the best candidates, they administered a nasal spray containing one of the custom-designed proteins to mice infected with influenza. This revealed complete protection from the flu if administered before 72 hours after exposure. The protection was similar or even better than provided by antibodies and did not trigger immune response.
Image: Artist impression of computer-designed mini protein binders targeting Influenza hemagglutinin. Image courtesy of Cognition Studio (Seattle) with assistance of Daniel-Adriano Silva and Lance Stewart/UW Medicine.