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.

Keywords: bioactivity; biosynthesis; heterologous expression; lasso peptides; medical application.

FIGURE 1

Four types of lasso peptides demonstrated by representative structures (class I, class II, class III, and class IV). Sviceucin: PDB code 2LS1 for class I, caulosegnin I: PDB code 2LX6 for class II, BI-32169: PDB code 3NJW for class III, LP2006: PDB code 5JPL for class IV. The macrolactam ring is colored in red, the tail is in blue, the disulfide bonds are in yellow.

FIGURE 2

(A) Representative lasso peptide biosynthetic gene clusters with a separate E and B protein or E-B fusion. (B) Proposed mechanism of lasso peptide biosynthesis, involving three steps.

FIGURE 3

Organization of commonly known lasso peptides from Actinobacteria, Proteobacteria, and Firmicutes (Solbiati et al., 1999; Knappe et al., 2008; Inokoshi et al., 2012; Maksimov et al., 2012b; Hegemann et al., 2013b, 2014; Maksimov and Link, 2013; Zimmermann et al., 2014; Zhu et al., 2016a; Kodani et al., 2018; Martin-Gomez et al., 2018; Su et al., 2019; Yu et al., 2020).

FIGURE 4

Structure of MccJ25 with indicated modifiable positions (PDB code: 1Q71). (A) The modifiable positions (V6, I13, F10, and F19) in the core peptide region of MccJ25 as a natural scaffold used for grafting four non-canonical amino acids (ncAAs) (Piscotta et al., 2015). (B) The modifiable positions (G12-I13-G14) in the core peptide region of MccJ25 as natural scaffold used for grafting the bioactive RGD peptide epitope (Knappe et al., 2011).