近日，美国默克公司Artis Klapars团队报道了生物催化级联可以制造大环肽烯醛酸酯。2026年5月7日出版的《科学》杂志发表了这项最新研究成果。

历史上，许多具有重要治疗价值的靶点只能通过注射用生物制剂来靶向。大环肽类分子——例如用于治疗动脉粥样硬化性心血管疾病的前蛋白转化酶枯草溶菌素/kexin 9型抑制剂enlicitide——正开始将这些靶点向口服给药疗法敞开大门，从而让更多患者能够受益。

研究组报道了enlicitide的汇聚式生物催化合成方法，通过一套工程化酶，以无保护基的方式催化选择性肽段形成、偶联和大环化反应。结合高效的结晶纯化（无需色谱分离），与先前的先进方法相比，该方法将合成步骤减少了超过一半，解决了长期存在的合成挑战，并为复杂肽类治疗药物的规模化、可持续开发提供了蓝图。

附：英文原文

Title: Biocatalytic cascades enable manufacture of the macrocyclic peptide enlicitide

Author: Artis Klapars, Anna Fryszkowska, Stephanie Galanie, Omer Ad, Ellen Y. Aguilera, Nnamdi Akporji, Chihui An, Stephanus Axnanda, Tewoderos M. Ayele, Richard S. Ayikpoe, Rodell C. Barrientos, Matthew R. Bauerle, Marc R. 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. GauthierJr., 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 M. 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, Bharath Krishnamurthi, Jeffrey T. Kuethe, Thomas T. Kwok, Alfred Y. Lee, Joshua Lee, Qiuhan Li, Shasha Li, Jing Liao, Wenjun Liu, Gurpreet Longia, Emma Madrigal, Peter E. Maligres, Kevin M. Maloney, Erin L. McCarthy, John A. McIntosh, Samaneh Mesbahi-Vasey, Margaret Miller, Mansi Modi, Jeffrey C. Moore, Debopreeti Mukherjee, Grant S. Murphy, Jennifer Victoriano Obligacion, Weilan Pan, Julia Parzecki, Anisha Patel, Teng Peng, Byron K. Peters, Tiffany Piou, Carlos A. Pons Siepermann, Christopher K. Prier, Akasha K. Purohit, Yangzhong Qin, Erik L. Regalado, Mikhail Reibarkh, Nelo R. Rivera, Sandra A. Robaire, Lee Robison, Syamantak Roy, Rebecca T. Ruck, Katie A. Rykaczewski, Christopher H. Schuster, Erica L. Schwalm, Andrew N. Singh, Eric Sirota, Alexandra C. Sun, Weijuan Tang, David A. Thaisrivongs, Nimisha Thakur, Weidong Tong, Van Truong, Ryan Tsoi, Qiang Tu, Ben W. H. Turnbull, Ophelia Ukaegbu, David A. Vargas, Juan E. Velasquez, Deeptak Verma, Heather Wang, Tao Wang, Xiao Wang, Ying Wang, Zhixun Wang, Matthew S. Winston, Chunyu Wu, Brian M. Wyvratt, Kai-Jiong Xiao, Yingju Xu, Jia-Xuan Yan, Hao Yang, Victoria Zhang, Yongqian Zhang, Michelle Zheng, Wendy Zhong

Issue&Volume: 2026-05-07

Abstract: 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.

DOI: aed8713

Source: https://www.science.org/doi/10.1126/science.aed8713