Organisms naturally incorporate a combination of only 20 to 22 unique amino acids in the synthesis of proteins. Proteins produced outside of this realm, from non-canonical amino acids, are known as xenoproteins and offer a few unique advantages. For one, they are more stable and can survive without refrigeration, unlike most protein drugs. A new MIT-led study published in PNAS highlights the development of a screening platform for rapidly engineering and testing synthetic xenoproteins.
“There is no other technological platform that can be used to create these xenoproteins because people haven’t worked through the ability to use completely nonnatural sets of amino acids throughout the entire shape of the molecule,” says senior co-author Brad Pentelute.
Starting with 16 “mirror-image” D-amino acid building blocks, the team engineered tens of millions of small proteins around 30 amino acids long. They then sought to identify proteins that would bind to a fluorescent-labeled IgG antibody against an influenza virus surface protein. To screen for active proteins, the team used a screening method that combined magnetic bead enrichment, flow cytometry analysis and high-throughput MS/MS-based sequencing. Within a few hours, the team had identified several active xenoproteins.
“The hope is that we can discover molecules in a rapid manner using this platform, and we can chemically manufacture them on demand. And after we make them, they can be shipped all over the place without refrigeration, for use in the field,” Pentelute says.
The team is now looking for xenoproteins that bind to other potential drug targets, with a long-term goal of rapidly synthesizing new drugs against emerging infectious diseases. Another item on the to-do list is the development “xenozymes,” xenoproteins capable of catalyzing novel types of chemical reactions.