Enlicitide is a molecule with massive potential. The oral drug candidate from Merck & Co. lowers cholesterol by inhibiting a protein called PCSK9—a target with a few therapies approved by the US Food and Drug Administration, all of which are injectables. But enlicitide is also a massive molecule, so making enough of the macrocyclic peptide to satisfy demand if it’s approved presents a huge challenge. Scientists at Merck & Co. now report a manufacturing route that uses a suite of enzymes to assemble enlicitide in a way that is both efficient and sustainable (Science 2026, DOI: 10.1126/science.aed8713).
“What this paper illustrates is the incredible power of biocatalysis to manufacture incredibly complex macrocyclic peptides,” says David A. Thaisrivongs, who leads the biocatalysis team in Merck & Co.’s process R&D group.
Thaisrivongs has been working on enlicitide’s synthesis for roughly a decade. He tells C&EN that the initial route developed by medicinal chemists was about 70 steps. “At the very beginning it was an extraordinary achievement to be able to even make a mg of a molecule this complicated,” he says. “If we had any hope of achieving our aspiration to democratize access to this molecule as an important medicine, we were going to have to invent a new way of manufacturing this molecule.”
Peptides have been made via solid-phase synthesis for more than 40 years. But, Thaisrivongs says, enlicitide couldn’t be made that way because the molecule contains motifs that aren’t amenable to that type of synthesis. Instead, the Merck & Co. scientists developed 13 enzymes that assemble the drug candidate on a multi-kg scale without the need for chromatography. The paper highlights a process that stitches enlicitide together in three biocatalytic cascades.
Godwin Aleku, who studies biocatalysis in drug discovery at King’s College London and was not involved with the work, says that he was particularly impressed with the Merck & Co. scientists’ use of adenosine triphosphate (ATP)–dependent amino acid ligases and thioesterases, which can be tricky enzymes. He was also surprised to see that enlicitide’s large molecular skeleton fit within some of these enzymes’ active sites.
“If we had any hope of achieving our aspiration to democratize access to this molecule as an important medicine, we were going to have to invent a new way of manufacturing this molecule.”
“Over the last few decades, we have really showcased the power of biocatalysis in small molecule synthesis, but we’ve not quite been able to make that big breakthrough into other drug modalities, like peptides,” Aleku says. “The field will be really excited about making this massive molecule,” he adds, particularly on an industrial scale.
Enzymes are likely to play a larger role in drug manufacturing as modalities that feature larger molecules, like antibody-drug conjugates, molecular glues, and protein degraders, become more broadly used, Thaisrivongs says. “We are just getting started on the kinds of chemical problems we can solve with biocatalysis in the pharmaceutical industry.”
2026 American Chemical Society
