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Biocatalytic cascades enable manufacture of the macrocyclic peptide enlicitide
Science. 2026 May 7;392(6798):643-647. doi: 10.1126/science.aed8713.
Artis Klapars
1, Anna Fryszkowska
1, Stephanie Galanie
1, Omer Ad
1, Ellen Y Aguilera
1, Nnamdi Akporji
1, Chihui An
1, Stephanus Axnanda
2, Tewoderos M Ayele
1, Richard S Ayikpoe
1, Rodell C Barrientos
2, Matthew R Bauerle
2, Marc R Becker
1, Kevin M Belyk
1, Lisa Bereznitski
3, Jackson K B Cahn
1, Karla Camacho Soto
1, Louis-Charles Campeau
1, Kevin R Campos
1, Anagha Chandra
1, Hsieh Yao Darryl Chang
1, Mengbin Chen
1, Zhiwei Chen
1, Wai Ling Cheung-Lee
1, Cheol K Chung
1, Stephanie W Chun
1, Sarah S Co
1, Ryan D Cohen
2, Stephen M Dalby
1, Guilherme Dal Poggetto
2, Truc Do
1, Spencer D Dreher
4, Riki J Drout
2, Noah P Dunham
1, Yi Fan
2, Ryan M Flessner
1, Jacob H Forstater
1, Scott P France
1, Janaka C Gamekkanda
1, Donald R Gauthier Jr
1, Agnieszka A Gil
1, Jacob W Greenwood
1, Noel Ha
2, Holst M Halsey
2, Xinxin Han
3, Michael Hartmann
4, Clara Hartmanshenn
1, Yu He
2, Edgar Hernandez
2, Kaori Hiraga
1, Hsing-I Ho
1, Cynthia M Hong
1, Alan Hruza
4, Hang Hu
2, Kari Hullen
2, Alan M Hyde
1, Tetsuji Itoh
1, Chey M Jones
4, Woo-Ok Jung
1, Kanan Kanuga
2, James Levi Knippel
1, Joshua N Kolev
1, Jongrock Kong
1, Birgit Kosjek
1, Sara Koynov
2, Michael H Kress
12, Bharath Krishnamurthi
1, Jeffrey T Kuethe
1, Thomas T Kwok
1, Alfred Y Lee
2, Joshua Lee
1, Qiuhan Li
1, Shasha Li
2, Jing Liao
3, Wenjun Liu
2, Gurpreet Longia
2, Emma Madrigal
1, Peter E Maligres
1, Kevin M Maloney
1, Erin L McCarthy
1, John A McIntosh
1, Samaneh Mesbahi-Vasey
4, Margaret Miller
3, Mansi Modi
2, Jeffrey C Moore
1, Debopreeti Mukherjee
2, Grant S Murphy
1, Jennifer Victoriano Obligacion
1, Weilan Pan
1, Julia Parzecki
1, Anisha Patel
2, Teng Peng
3, Byron K Peters
1, Tiffany Piou
1, Carlos A Pons Siepermann
1, Christopher K Prier
1, Akasha K Purohit
2, Yangzhong Qin
2, Erik L Regalado
2, Mikhail Reibarkh
2, Nelo R Rivera
2, Sandra A Robaire
3, Lee Robison
2, R. David Row
1, Syamantak Roy
2, Rebecca T Ruck
1, Katie A Rykaczewski
1, Christopher H Schuster
1, Erica L Schwalm
2, Andrew N Singh
2, Eric Sirota
2, Alexandra C Sun
1, Weijuan Tang
2, David A Thaisrivongs
1, Nimisha Thakur
2, Weidong Tong
2, Van Truong
2, Ryan Tsoi
1, Qiang Tu
2, Ben W H Turnbull
1, Ophelia Ukaegbu
2, David A Vargas
1, Juan E Velasquez
1, Deeptak Verma
1, Heather Wang
2, Tao Wang
1, Xiao Wang
2, Ying Wang
2, Zhixun Wang
1, Matthew S Winston
1, Chunyu Wu
1, Brian M Wyvratt
1, Kai-Jiong Xiao
1, Yingju Xu
1, Jia-Xuan Yan
2, Hao Yang
1, Victoria Zhang
1, Yongqian Zhang
2, Michelle Zheng
1, Wendy Zhong
2
Affiliations
1. Process Research and Development, Merck & Co., Inc., Rahway, NJ, USA.
2. Analytical Research and Development, Merck & Co., Inc., Rahway, NJ, USA.
3. Global Science, Engineering, and Commercialization, Merck & Co., Inc., Rahway, NJ, USA.
4. Discovery, Preclinical, and Translational Medicine, Merck & Co., Inc., Rahway, NJ, USA.
Historically, many compelling therapeutic targets have been accessible only by injectable biologic drugs. Macrocyclic Peptides, such as the proprotein convertase subtilisin/kexin type 9 inhibitor enlicitide for the treatment of atherosclerotic Cardiovascular Disease, are beginning to unlock these targets to orally administered therapies to enable broader patient access. We report the convergent biocatalytic assembly of enlicitide from simple building blocks enabled by a suite of engineered Enzymes to catalyze selective peptide fragment formation, coupling, and macrocyclization in a protecting group-free manner. Together with efficient crystallizations that obviate the need for chromatography, this approach reduces the number of steps by greater than half compared with prior state-of-the-art methods, addressing long-standing synthetic challenges and offering a sustainable blueprint for the scalable development of complex peptide therapeutics.
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