Progress and Challenges in the Biosynthesis and Chemical Synthesis of Lasso Peptides

Lasso peptides have emerged as a promising class of ribosomally synthesized and post-translationally modified peptide natural products, with entangled slipknot-like structures produced through multienzyme biosynthetic pathways. Their threaded structure provides exceptional thermal and proteolytic stability, along with diverse biological activities, especially against infectious diseases and cancer. Over the past two decades, making the native lasso fold through chemical synthesis has been considered a paramount challenge that is not yet solved. Nevertheless, in recent years, there has been significant progress in overcoming technical barriers associated with the discovery and development of lasso peptides that unlock their broader potential. In this perspective, we outline recent advances in the production of lasso peptides via biosynthesis and chemical synthesis approaches, as well as late-stage modification strategies to introduce chemical diversity onto recombinantly produced lasso peptides. We conclude by discussing remaining challenges and opportunities for further advances in this field.