SE5:E3: A Process Chemist's Romance with Scaling a Macrocyclic Peptide

Last episode, we watched medicinal chemistry dream up enclitide (MK-0616) — this week we find out what happens when someone actually has to make it. Dani and LC are joined by David Thaisrivongs and Gao Shang to unpack their recent JACS paper on the total synthesis of enlicitide, a macrocyclic peptide complex enough to keep company with taxol, vancomycin, and eribulin. Along the way they get into the pivot from solid-phase to solution-phase peptide synthesis, the perpetual headache of sourcing non-canonical amino acids and how biocatalysis cracked it open, and the crystallization detective work that let the team ditch chromatography entirely. There's also a great discussion on why a late-stage macrolactamization became a late-stage RCM — the kind of route decision that looks obvious only in hindsight.

Fair warning: this one was among JACS's top-accessed papers of 2025, so you're in good company!

If you enjoyed this chapter of the enlicitide story, stay tuned—we've got plenty more peptide chemistry, process development adventures, and behind-the-scenes drug discovery stories coming your way this season.

Read some of the papers we discussed today:

Total Synthesis of Enlicitide Decanoate - ⁠⁠J. Am. Chem. Soc.⁠⁠

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