Artis Klapars, Anna Fryszkowska, Stephanie Galanie, Omer Ad, Ellen Y. Aguilera, Nnamdi Akporji, Chihui An, Stephanus Axnanda, Tewoderos M. Ayele, Richard Ayikpoe, Rodell C. Barrientos, Matthew R. Bauerle, M. Becker, Kevin M. Belyk, Lisa Bereznitski, Jackson K. B. Cahn, Karla Camacho Soto, Louis‐Charles Campeau, Kevin R. Campos, Anagha Chandra, Hsieh Yao Darryl Chang, Mengbin Chen, Zhiwei Chen, Wai Ling Cheung‐Lee, Cheol K. Chung, Stephanie W. Chun, Sarah S. Co, Ryan D. Cohen, Stephen M. Dalby, Guilherme Dal Poggetto, Truc Do, Spencer D. Dreher, Riki J. Drout, Noah P. Dunham, Yi Fan, Ryan M. Flessner, Jacob H. Forstater, Scott P. France, Janaka C. Gamekkanda, Donald R. Gauthier, Agnieszka A. Gil, Jacob W. Greenwood, Noel Ha, Holst M. Halsey, Xinxin Han, Michael Hartmann, Clara Hartmanshenn, Yu He, Edgar Hernandez, Kaori Hiraga, Hsing‐I Ho, Cynthia Hong, Alan Hruza, Hang Hu, Kari Hullen, Alan M. Hyde, Tetsuji Itoh, Chey M. Jones, Woo-Ok Jung, Kanan Kanuga, James Levi Knippel, Joshua N. Kolev, Jongrock Kong, Birgit Kosjek, Sara Koynov, Michael H. Kress, B. Krishnamurthi, Jeffrey T. Kuethe, Thomas T. Kwok, Alfred Y. Lee, Joshua Lee, Qiuhan Li, S Li, Jing Liao, Wenjun Liu, Gurpreet Longia, Emma Madrigal, Peter E. Maligres, Kevin M. Maloney, Erin L. McCarthy, John McIntosh, Samaneh Mesbahi‐Vasey, Margaret Miller, Mansi Modi, Jeffrey C. Moore, Debopreeti Mukherjee, G. Murphy, Jennifer V. Obligacion, W Pan, Julia Parzecki, Anisha Patel, Peng Teng, Byron K. Peters, Tiffany Piou, Carlos A. Pons Siepermann, Christopher K. Prier, Akasha K. Purohit, Yangzhong Qin, Erik L. Regalado, Mikhail Reibarkh
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.