Ligase enzymes for the synthesis of peptide therapeutics

Peptides are widely used as therapeutics and in many other important applications. However, current chemical synthesis of peptides is highly step- and atom-inefficient, requiring deleterious reagents and solvents, which creates harmful waste. Alternative methods for more sustainable enzymatic peptide synthesis would be highly desirable. However, most enzyme systems used in nature for peptide biosynthesis are difficult to reconstitute in vitro , and therefore impractical for the synthesis of non-natural peptide targets. Recently, researchers have uncovered an increasing number of smaller amide bond synthetases (ABS) and ATP-grasp ligases (AGL), enzymes involved in the biosynthesis of small microbial peptide natural products. These simpler stand-alone ATP-dependent ligases are robust biocatalysts with great potential for the controlled synthesis of peptides, particularly short peptides armed with reactive “warhead” functionalities. Here, we highlight the discovery of new ABS and AGL enzymes involved in peptide natural product biosynthesis, and their use in the synthesis of therapeutically relevant peptides.