Biocatalytic cascades enable manufacture of the macrocyclic peptide enlicitide.
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| Title: | Biocatalytic cascades enable manufacture of the macrocyclic peptide enlicitide. |
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| Authors: | Klapars, Artis (AUTHOR), Fryszkowska, Anna (AUTHOR), Galanie, Stephanie (AUTHOR), Ad, Omer (AUTHOR), Aguilera, Ellen Y. (AUTHOR), Akporji, Nnamdi (AUTHOR), An, Chihui (AUTHOR), Axnanda, Stephanus (AUTHOR), Ayele, Tewoderos M. (AUTHOR), Ayikpoe, Richard S. (AUTHOR), Barrientos, Rodell C. (AUTHOR), Bauerle, Matthew R. (AUTHOR), Becker, Marc R. (AUTHOR), Belyk, Kevin M. (AUTHOR), Bereznitski, Lisa (AUTHOR), Cahn, Jackson K. B. (AUTHOR), Soto, Karla Camacho (AUTHOR), Campeau, Louis-Charles (AUTHOR), Campos, Kevin R. (AUTHOR), Chandra, Anagha (AUTHOR) |
| Source: | Science. 5/7/2026, Vol. 392 Issue 6798, p643-647. 5p. |
| Subjects: | Biocatalysis, Cyclic peptides, Coronary artery disease, Peptide synthesis, Sustainability, Peptide drugs, Enzyme biotechnology, Drug development |
| 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. Editor's summary: Macrocyclic peptides are formed by linking together parts of a peptide, which provides conformational rigidity, binding specificity, and protease resistance that make these molecules attractive for drug design. Chemical synthesis of these peptides can be very challenging due to their complex structure and the potential for competing reactions. Klapars et al. developed a biocatalytic approach to produce the complex macrocyclic drug enlicitide, which is under investigation for the prevention of atherosclerotic cardiovascular disease (see the Perspective by Buller and Pelletier). Using ATP-dependent ligases and transacylation by a hydrolase, the authors assembled a large fragment containing the first macrolactam ring. They then combined this fragment with two chemically synthesized fragments in a five-enzyme cascade and a chemoenzymatic step. The resulting synthesis is exceptionally efficient, avoids protecting groups, and is optimized for multikilogram-scale production with an overall yield of around 40%. —Michael A. Funk [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| 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. Editor's summary: Macrocyclic peptides are formed by linking together parts of a peptide, which provides conformational rigidity, binding specificity, and protease resistance that make these molecules attractive for drug design. Chemical synthesis of these peptides can be very challenging due to their complex structure and the potential for competing reactions. Klapars et al. developed a biocatalytic approach to produce the complex macrocyclic drug enlicitide, which is under investigation for the prevention of atherosclerotic cardiovascular disease (see the Perspective by Buller and Pelletier). Using ATP-dependent ligases and transacylation by a hydrolase, the authors assembled a large fragment containing the first macrolactam ring. They then combined this fragment with two chemically synthesized fragments in a five-enzyme cascade and a chemoenzymatic step. The resulting synthesis is exceptionally efficient, avoids protecting groups, and is optimized for multikilogram-scale production with an overall yield of around 40%. —Michael A. Funk [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.aed8713 |
