With $4.5 million raised in a seed round, San Diego-based startup Lassogen is poised to demonstrate that lasso peptides are a powerful new class of therapeutics for disease targets that thwart traditional approaches like small molecule drugs and antibodies.
Lasso peptides, also known as lasso knots, are an unusual class of ribosomally synthesized and posttranslationally modified peptides (RiPPs) [1] characterized by a unique interlocked knot-like topology that encircles a seven to nine N-terminal amino acid residues in a macrolactam ring. The resulting unique lariat-like threaded structure endows most lasso peptides with exceptional stability against physical and chemical degradation, including proteases.
The biosynthesis of lasso peptides is typically accomplished in three steps with the precursor peptide A recognizing and binding to the RRE protein and then being cleaved by CanB to release the leader peptide, followed by CanC catalyzing core peptide macrolactam cyclization and maturation [2]. Lasso peptides can also be extensively modified using PTMs such as methylation, acetylation, phosphorylation, disulfuration, C-terminal thiolation and N-terminal acetylation.
These unique structural properties and diverse physiological functions have fueled extensive research on lasso peptides, including a growing library of synthetic lasso peptides, as well as an ever-increasing number of studies exploring the interaction of tailored lasso peptides with biological targets. However, there remains a need to better understand the underlying molecular mechanisms that determine their unusual thermal and enzymatic stabilities and to improve heterologous expression systems for large-scale production of lasso peptides. This will allow for the mining of unforeseen intrinsic physiologic properties that could have therapeutic applications.