Among natural products, lasso peptides are unique in that they are highly stable and easily engineerable. These features make lasso peptides ideal candidates as molecular scaffolds for the development of therapeutic drugs. Recent advances in genomics, bioinformatics, and chemical analytics have greatly facilitated the discovery of lasso peptides in nature. As the number of lasso peptide biosynthetic gene clusters (BGCs) continues to increase, the need for efficient heterologous expression and structural analysis becomes increasingly pressing.
In this context, a promising approach has been to use a combination of site-selective chemical modification of the coding sequences of the BGC and heterologous expression in Streptomyces. This has led to the production of several lasso peptides, including specialicin, achromosin, and sphaericin. The latter two have been found to possess disulfide bond formation functions shared by a thioredoxin domain and a cysteine oxidoreductase domain that are homologous to the corresponding proteins in four other class I lasso peptides.
To further facilitate the work on lasso peptides, Mitchell and colleagues have recently introduced an RODEO-enabled approach for selecting a bacterial host strain for heterologous expression of a selected lasso peptide BGC. This has led to the identification of a new producing strain for anantin, which possesses a novel architecture featuring a disulfide bonded macrocycle in its C-terminal tail. Additionally, they have identified a novel lasso peptide produced by the same strain, named LP2006, with an unusual structure consisting of an alternating arginine- and asparagine-containing core.