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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⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠⁠⁠⁠⁠

What happens when the textbook SAR playbook stops working? On this episode of Pharm to Table, Rob Garbaccio joins Dani and LC to share the discovery story behind enlicitide (MK-0616), a journey filled with unusual SAR, creative problem-solving, and plenty of chemistry twists along the way. From issue-driven drug design to non-canonical amino acids and modular synthesis strategies, this conversation offers a behind-the-scenes look at how real medicines are discovered. If you're training as a chemist today, this is a story you won't want to miss.

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:

Discovery Process of Enlicitide, a Highly Engineered Macrocyclic Peptide Therapeutic, through Issue-Driven Fragment-Based Synthetic Assembly and SAR - ⁠J. Med. Chem.⁠

Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod

⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠⁠⁠⁠

To kick off Season 5, Dani and LC discuss a recent perspective published in the Journal of Organic Chemistry that highlights innovations in synthetic chemistry which trace their origins to the work of discovering, developing and commercializing novel therapeutics. This publication was the most accessed paper published in JOC in 2025!

Dani and LC explore the motivations on writing it, its main thesis and lesson learned from reexamining nearly 75 years of chemistry innovations at Merck.

Be sure to listen through to the very end for a special Season 5 theme reveal!

Read and listen to some of the papers we discussed today:

From Cortisone to Enlicitide: A Journey of Synthetic Chemistry Innovations at Merck

Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod

⁠⁠⁠⁠Visit our website at ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠⁠⁠⁠⁠