Peptide synthesis can create valuable therapeutics. One example is synthetic insulin. Nonetheless, peptide-based therapeutics face a range of challenges, including the inability to cross the cell membrane, the potential for proteolysis, and constrained biochemical space. To solve those problems, researchers can use peptidomimetics, which are protein analogues. Recently, a team of scientist described a cell-free method of synthesizing peptidomimetics.

“Cell-free protein synthesis offers exciting benefits for making peptidomimetic drugs because of the freedom of design to incorporate non-canonical chemistries when working without the constraints of living organisms,” says one of the authors, Michael Jewett, PhD, professor of bioengineering at Stanford University (formerly at Northwestern University). “Put another way, we are able to repurpose the molecular machinery of the cell to make new-to-nature products that have therapeutic benefit.”

Michael Jewett, PhD

In cell-free synthesis, “recent advances have shown that the ribosome and associated machinery for translation are more promiscuous for noncanonical substrates than we previously thought,” Jewett says. “Key recent advances have been to demonstrate the capability of the ribosome to incorporate novel amino acids, like β- and γ-cyclic amino acids, as well as alternative monomers like thioacids.”

In fact, Jewett and his colleagues keep finding new capabilities in using cell-free synthesis to make peptidomimetics. “We even just showed ribosome-mediated biosynthesis of pyridazinone oligomers, a novel bond that provides new backbone linkages,” he says. “When considering advances to engineer the ribosome to work more efficiently with these substrates, it’s a really exciting time.”

Such work, though, already goes beyond the lab. “Cell-free synthesis of peptidomimetic drugs is already being used by industry for screening and identifying new therapeutics,” Jewett says. “Looking ahead, continued advances in lowering costs and scaleup could make possible new biomanufacturing practices as well.”

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