The February BPS Journal Club explores lasso peptides, a fascinating class of bioactive macrocyclic peptide natural products. These peptides have a unique structure with a threaded (rotaxane) motif, where the C-terminal tail is captured within a macrolactam through an isopeptide bond. The lasso fold provides pharmacokinetic advantages, including high proteolytic and metabolic stability, along with resistance to degradation. This defined structure can be utilized to optimize interactions with therapeutically relevant targets.
Chemical synthesis of lasso peptides poses a significant challenge, as the nonthreaded isomer (referred to as a tadpole isomer) is kinetically favored over forming the lariat knot-like fold. While companies like Lassogen are making significant progress with engineered therapeutic lasso peptides (Lassotides™), reliance on biosynthetic routes limits the incorporation of noncanonical amino acids and other structural investigations.
A team led by Professor Andrew G. Roberts at the University of Utah recently reported the solid-phase peptide synthesis of cyclic, cyclic-branched (tadpole), and linear isomers of sungsanpin and ulleungdin, lasso peptide natural products known to inhibit cell migration in models of metastasis (https://pubs.acs.org/doi/10.1021/acschembio.3c005251). Prof. Roberts and collaborators discovered that the lasso motif itself was not critical for inhibition of cell migration by synthetically accessible analogs of these natural products.
In their publication, the Roberts group details a general approach to the SPPS and on-resin cyclization of lasso peptide isomers and highlights the use of Fmoc-Asp(CSY)−OH (CAS 2379679-90-8) to mask the carboxylic acid functionality of Asp in certain aspartimide prone sequences. So, while the class II lasso scaffold remains a synthetic challenge yet to be overcome, the Roberts group and collaborators remind us that promising hits can be obtained from evaluating structurally complex natural molecules and applying ingenuity in peptide design to discover chemically tractable leads.
1. Nonthreaded Isomers of Sungsanpin and Ulleungdin Lasso Peptides Inhibit H1299 Cancer Cell Migration; Lori Digal, Shiela C. Samson, Mark A. Stevens, Abhijit Ghorai, Hyungyu Kim, Marcus C. Mifflin, Keith R. Carney, David L. Williamson, Soohyun Um, Gabe Nagy, Dong-Chan Oh, Michelle C. Mendoza, and Andrew G. Roberts. ACS Chemical Biology 2024 19 (1), 81-88. DOI: 10.1021/acschembio.3c00525
Wendy Hartsock
Member, BPF Scientific Advisory Board
https://www.linkedin.com/in/wendy-hartsock-49938512/