Lasso Peptides as Versatile Scaffolds for Peptide Engineering

Objetivo

The rise of antimicrobial resistance and the limits of conventional therapeutics call for new molecular scaffolds with high stability, specificity, and tunable function. Cyclic peptides offer this potential, combining protein-like binding with small-molecule stability. Among them, lasso peptides stand out for their knotted topology, which confers exceptional resistance to proteolytic degradation and enables diverse biological activities. Produced by many organisms as natural defense molecules, they represent promising scaffolds for therapeutic discovery. Yet, despite their abundance and diversity, their potential remains largely untapped due to key challenges: limited incorporation of non-canonical amino acids, poor cell permeability, and the absence of strategies for generating chemically diverse libraries suitable for high-throughput screening.

LASSOVERSE will address these challenges by establishing a platform for engineering lasso peptides beyond their natural sequence space. The project focuses on three goals: (i) elucidating the enzymatic mechanism of lasso maturation to improve catalytic efficiency and folding kinetics; (ii) expanding sequence and structural diversity through incorporation of non-natural residues and backbones, enabling library synthesis and epitope grafting; and (iii) enhancing cellular uptake by generating chemoenzymatically synthesized, cell-permeable antimicrobial candidates.

By integrating chemical synthesis, enzymatic maturation, and rational design, LASSOVERSE will uncover fundamental principles of lasso peptide biosynthesis and structure–function relationships, transforming these natural products into a versatile platform for next-generation antimicrobial and therapeutic development.