SE5:E4 - Part 1: Protecting Groups? We Need to Talk: Manufacturing MK-0616 with Enzyme Cascades

How do you design a manufacturing process for a molecule as complex as MK-0616? In Part 1 of this Pharm to Table series, Dani and LC join Stephanie Galanie, Director in Biocatalysis, and Artis Klapars, Distinguished Scientist in Process Chemistry, to discuss the manufacturing route behind their Science paper on biocatalytic cascades for this macrocyclic peptide.

We start with a central question: why develop a new synthesis when an existing route already delivers hundreds of kilograms? Artis and Stephanie explain how the team worked backward from MK-0616’s complex structure to choose key disconnections, then developed three interconnected cascades to assemble it. Along the way, we unpack the tools behind those decisions, including directed evolution and enzymes that selectively form amide bonds without relying on protecting groups.

Part 2 takes us inside the cascades, from four enzymes working in one vessel to fragment ligation and macrocyclization, then tackles the final challenge: isolating MK-0616 in the right purity and salt form.

Read some of the papers we discussed today:

Biocatalytic cascades enable manufacture of the macrocyclic peptide MK-0616 - ⁠Science⁠

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