Biocatalytic cascades enable manufacture of the macrocyclic peptide enlicitide
Summary
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
Content
# Biocatalytic cascades enable manufacture of the macrocyclic peptide enlicitide
*Published: 2026 May 7*
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: 10.1126/science.aed8713