SE5:E2: The Macrocyclic Mullet: The Story of Enlicitide
7/15/202627 min
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.*
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Clips
Transcript preview
First 90 secondsRob Garbaccio· Guest0:00
And so if you think about it in that context, you've got the business end of the molecule that really we didn't change very much in this paper at all because that was making those key contacts to the protein business up front. And then we could party a little bit in the back with the crosslinks because all we were trying to do- Like a mullet? Yes. [laughs] Yes, exactly.
Dani Schultz· Host0:16
Are you trying to say inlicitide is like a mullet?
Rob Garbaccio· Guest0:19
Listen, I grew up- Oh my God ... I grew up, I grew up in the early '90s, so I know, I know a good mullet when I see one.
L.-C. Campeau· Host0:24
Hi, I'm LC, and I'm a storyteller. I'm a passionate chemist who loves to explore and tell stories about how chemistry can change the world.
Dani Schultz· Host0:32
And I'm Dani, and I'm LC's spirited chemistry co-host. I love to bring high energy and positivity to my chemistry, but also my life. Welcome to the Pharm to Table podcast.
L.-C. Campeau· Host0:43
We're two chemists working at the pharmaceutical company Merck in the US.
Dani Schultz· Host0:53
Also known as MSD everywhere else in the world, except Canada, the US, and its territories.
L.-C. Campeau· Host0:59
And this is a podcast where we'll tell you stories about the people and the science behind the papers published by our chemistry group.
Dani Schultz· Host1:07
Each week, we'll pick one to two papers that we've recently published and introduce you to the key people behind it, and also ask them to give you a unique insight into the story behind it.
L.-C. Campeau· Host1:17
Hello, listeners. We are here today with, uh, Rob Garbaccio, the head of medicinal chemistry here at Merck, and we're gonna talk about the discovery