2026/05/07 by Artis Klapars, Anna Fryszkowska, Stephanie Galanie +97 · 1 voice
Biochemistry, Genetics and Molecular Biology · Chemistry · #Biocatalysis #Biochemical and Structural Characterization #Blueprint #Chemical Synthesis and Analysis #Click Chemistry and Applications #Cyclic peptide #Enzyme #Peptide #Proprotein convertase
paper · doi:10.1126/science.aed8713
openalex publication_date 2026/05/07 · openalex created_date 2026/05/08 · openalex updated_date 2026/08/05
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.