Cinnamoyl-containing non-ribosomal peptides: discovery, bioactivity and biosynthesis.

Covering: up to Oct, 2025Cinnamoyl-containing non-ribosomal peptides (CCNPs) are characterized by a cinnamoyl group, which is substituted at the ortho position with an alkyl side chain and linked to a peptide scaffold, representing a structurally unique and pharmacologically promising family of microbial natural products. Here, the current knowledge of their chemical diversity, biological activities, and intricate biosynthetic mechanisms is systematically summarized. Their characteristic biosynthetic logic centers on the conserved coupling of a highly reducing type II polyketide synthase (hrPKS II) with a non-ribosomal peptide synthetase (NRPS). Particular emphasis is placed on two fundamental principles: first, the conserved pathway for cinnamoyl benzene ring formation, initiated by an isomerase and proceeding via 6π-electrocyclization catalyzed by three distinct enzymes classes, namely, YsfF (4-hydroxybenzoyl-CoA thioesterase (4-HBT)-like enzymes), Kcn17-19 (DsrE family enzyme components) and YssX/YsfX, thereby providing a reliable signature for genome mining. Second, the remarkable diversity of cinnamoyl tailoring, peptide modification, and NRPS assembly collectively offers substantial opportunities for structural diversification through combinatorial biosynthesis strategies. Elucidating these biosynthetic features has shifted the research paradigm from discovery to rational engineering. However, this shift has not yet translated into comprehensive pharmacological evaluation, as most reported activities have been only briefly assessed, and extensive studies are still needed to fully realize their therapeutic potential. This review not only consolidates recent advances but also provides a strategic framework for future research aimed at unlocking the full potential of these fascinating natural products.