Software-designed miniproteins could create new class of drugs – Science

Scientists have built their own “mini-antibodies” using software that predicts how proteins fold. The advance could enable development of a new class of drugs to fight everything from cancer to COVID-19.
“It’s pretty amazing stuff,” says Steven Mayo, a chemist at the California Institute of Technology who wasn’t involved in the study. The software should also allow researchers to design diagnostic probes that could detect diseases early in the body, adds Tanja Kortemme, a bioengineer at the University of California, San Francisco, also not involved. “It opens up many possibilities.”
Antibodies excel at binding to proteins, such as those on invading microbes, so pharmaceutical companies use them as drugs to battle infections and cancer. But because antibodies are large proteins, they are costly to make and often unstable. Researchers have been working to make miniature versions of these binders that are cheaper and often more stable. But designing them to bind specific targets has been difficult.
When antibodies bind to a target, it’s like a rock climber trying to scale a sheer cliff face, explains David Baker, a computational structural biologist at the University of Washington (UW), Seattle: The surface is mostly smooth with few hand- and footholds. Antibodies are large. So, they can snag many weak holds simultaneously, which collectively allows them to hold firm to a target.
Miniproteins have fewer options. Researchers have tried to overcome this deficiency by identifying hot spots on proteins—strong handholds—and then build miniproteins around that hold. That only works for a handful of targets studied enough that their hot spots have been scoped out, however.
To get around this problem, Baker and his colleagues turned to Rosetta, software they designed to predict protein structures based on their amino acid sequence. To create a map of potential handholds, the team instructed the program to first calculate how tightly specific amino acids would bind to different spots across the surface of a target protein. The software then looked for clusters of neighboring handholds and determined how to build a stable miniprotein that would grab onto as many holds in a cluster as possible. The researchers used the software to construct tens of thousands of virtual minibinders and compared their calculated binding.
Baker and his colleagues tested their strategy on 12 target proteins, including proteins involved in cancer and proteins on the surfaces of viruses such as influenza and SARS-CoV-2. Yeast turned these virtual binders into actual miniproteins. Further modification enabled the team to make these proteins even more sticky. For each of their 12 targets, the researchers wound up with miniproteins that bound as strongly as, if not stronger than, most antibodies do, they report today in Nature.
Because many of the targets play roles in disease, the minibinders show potential as medicines, the researchers say. In July 2021, for example, Baker and his colleagues reported an early example of their method in a preprint. It produced miniproteins that bind to and neutralize the spike protein of SARS-CoV-2, the virus that causes COVID-19. The compounds were then shown to protect genetically engineered mice that express a human version of the protein that the virus latches onto. Clinical trials may begin this year, Baker says.
“We can design proteins to bind to any target,” says co-author Longxing Cao, a postdoc at UW. So miniproteins could not only block disease proteins, he says, but also direct toxic payloads to cancerous tissues, or ferry light-emitting or radioactive diagnostic molecules to cancer or other disease cells, to indicate the progress of treatment.
Still, “There is room for improvement,” Baker says. Despite Rosetta’s predictions, many miniproteins didn’t stick to their target. But the software will continue to make adjustments, he says, so its designs are sure to improve over time.
Bob is a news reporter for Science in Portland, Oregon, covering chemistry, materials science, and energy stories.
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