Biocatalytic synthesis of peptidic natural products and related analogues

Peptidic natural products (PNPs) represent a rich source of lead compounds for the discovery and development of therapeutic agents for the treatment of a variety of diseases. However, the chemical synthesis of PNPs with diverse modifications for drug research is often faced with significant challenges, including the unavailability of constituent nonproteinogenic amino acids, inefficient cyclization protocols, and poor compatibility with other functional groups. Advances in the understanding of PNP biosynthesis and biocatalysis provide a promising, sustainable alternative for the synthesis of these compounds and their analogues. Here we discuss current progress in using native and engineered biosynthetic enzymes for the production of both ribosomally and nonribosomally synthesized peptides. In addition, we highlight new in vitro and in vivo approaches for the generation and screening of PNP libraries.