Cebulassopins, Antiproliferative Lasso Peptides from a Split Biosynthetic Operon

Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides distinguished by their lasso-like, threaded topology. Common to all lasso peptides biosynthetic gene clusters examined so far is an arrangement whereby the precursor peptide is encoded adjacent to the macrolactam synthetase and other modification genes. Here we report the cebulassopins A-D (1-4), the first example of lasso peptides synthesized by a split operon whereby multiple precursors are encoded several Mbps distant from the modification enzymes. Aside from characterizing their structures and calculating the three-dimensional topology of 1 and 2, we also find that the cebulassopins are potent antiproliferative agents with sub-μM inhibitory concentrations against human lung carcinoma cells. These results set the stage for further biological examination and exploration of other split lasso peptide gene clusters.