Lasso Peptides: Heterologous Production and Potential Medical Application

Abstract

Lasso peptides are natural products found in bacteria. They belong to a specific family of ribosomally-synthesized and posttranslationally-modified peptides with an unusual lasso structure. Lasso peptides possess remarkable thermal and proteolytic stability and various biological activities, such as antimicrobial activity, enzyme inhibition, receptor blocking, anticancer properties and HIV antagonism. They have promising potential therapeutic effects on gastrointestinal diseases, tuberculosis, Alzheimer's disease, cardiovascular disease, fungal infections and cancer. Lasso peptides with high stability have been shown to be good carriers for other bioactive peptides. These make them attractive candidates for pharmaceutical research. This review aimed to describe the strategies used for the heterologous production of lasso peptides. Also, it indicated their therapeutical potential and their capacity to use as an efficient scaffold for epitope grafting.

Rational generation of lasso peptides based on biosynthetic gene mutations and site-selective chemical modifications

“…2 and S8), suggesting that mutations at these positons can be tolerated by the downstream processing proteins StlaB1/B2/C. Cells expressing the L1A and A7G variants produced lasso peptide derivatives L1A (10) and A7G (11), which the HPLC data suggested were produced at much reduced yields compared to 1. Even lower product yields were detected from cells expressing the D8E, W9A, and W9R variants (these putative products could only be detected by LC-MS, Figs.…”

“…[1][2][3][4] Owing to this threaded fold, lasso peptides exhibit resistance to heat, 5 denaturing agents, 6 and proteases 6 (with the notable exception of lasso peptide isopeptidases [7][8][9][10] ). These thermal and proteolytic stabilities, viewed alongside their variously reported biological activities (e.g., antibacterial, anticancer and anti-HIV activities), 1,11 have garnered strong interest in pursuing lasso peptides as drug leads with desirable pharmacokinetic properties. For example, by introducing a tripeptide Arg-Gly-Asp (RGD) motif to the MccJ25 lasso peptide, this engineered MccJ25 derivative acquires potent binding affinity for integrins (with IC50 values in nanomolar range) and can inhibit capillary formation of human umbilical vein endothelial cells (HUVECs).…”

Discovery of the Class I Antimicrobial Lasso Peptide Arcumycin

“…Lasso peptide biosynthesis requires four proteins for production and maturation of the natural product: 1) the precursor peptide, comprised of the leader peptide that is recognized by tailoring proteins and the core peptide that contains the primary amino acid sequence of the mature natural product; 2) a lasso cyclase, which forms the isopeptide macrocyclic bond within the core peptide; 3) the RiPP recognition element, which binds to the leader peptide; and 4) the leader peptidase, which cleaves the leader peptide from the core peptide. [45], [46] To explore structural diversity directly related to lasso peptide sequence, we elected to use the precursor peptide from each of the twelve characterized antimicrobial lasso peptides as queries in alignment searches. We conducted BLASTp [47] searches against the NCBI database for each of the precursor peptides, and all resulting sequences query were collected as preliminary hits.…”

Biocatalytic synthesis of peptidic natural products and related analogues

“…We will not discuss these types of cyclization, as their biocatalytic applications have been developed to a less extent, in comparison with lanthipeptides and microviridins. On the other hand, lasso peptides consist of a macrolactam formed between the N -terminus of the peptide and a carboxylate sidechain in an ATP-dependent manner, and the production of these peptides with synthetic and biocatalytic methods has been reported previously ( Cheng and Hua, 2020 ; Hegemann et al., 2015 ; Maksimov et al., 2012 ; Si et al., 2020 ).…”