Emulating nonribosomal peptides with ribosomal biosynthetic strategies

Abstract

This review compares structural features common to both nonribosomal and ribosomally synthesised and posttranslationally modified peptides and describes recent advances for using the RiPP technology to mimic nonribosomal peptides.

Cyclic Peptides for Drug Development

“…Ribosomal synthesis polymerizes the 20 canonical amino acids using a DNA template, and nonribosomal synthesis employs enzyme complexes to also connect non-canonical amino acids for even more diverse structures. [32] The efficient coupling of amino acids to long polymers could be replicated in the lab using chemical reactions. [33] While nature synthesizes peptides from the Nterminus in the direction of the C-terminus, the opposite direction is generally more efficient for chemical peptide synthesis.…”

“…For peptides specifically, nature has evolved two different methods for polymerizing the amino acid monomer: ribosomal and non‐ribosomal synthesis. Ribosomal synthesis polymerizes the 20 canonical amino acids using a DNA template, and non‐ribosomal synthesis employs enzyme complexes to also connect non‐canonical amino acids for even more diverse structures [32] . The efficient coupling of amino acids to long polymers could be replicated in the lab using chemical reactions [33] .…”

Genome Mining for New Enzyme Chemistry

“…Many RiPPs are macrocyclic structures that possess favorable physiochemical properties such as higher metabolic stability, cell membrane permeability, and reduced entropy cost upon target binding compared to the corresponding linear peptides. , Numerous RiPP enzymes possess broad substrate specificity, enabling catalysis on unnatural substrates to accelerate early drug discovery. ,− Consequently, libraries of RiPPs have been developed and screened against disease-relevant protein targets, yielding new-to-nature RiPPs as potential drug candidates. ,− …”

Beyond 20 in the 21st Century: Prospects and Challenges of Non-canonical Amino Acids in Peptide Drug Discovery

“…5 The inspiration for applying non-canonical amino acids (ncAAs) to macrocyclic peptide drug discovery has origins in peptide natural products, specifically non-ribosomal peptides (NRPs) and ribosomally synthesized and post-translationally modified peptides (RiPPs). 6 Notable examples include cyclosporin A (an NRP) and, most recently, darobactin A (a RiPP), 7 where biological activity can be attributed to multifaceted, unique AA architectures (Figure 1A). 8 While ncAAs are established in small molecule and peptidomimetic drug discovery, 9 not until recently have advances in affinitybased hit-finding platforms, such as mRNA display, provided a means to generate >10 12 unique de novo ncAA-containing macrocyclic peptides (ncAA-MPs) in a single round of screening.…”

“…The inspiration for applying non-canonical amino acids (ncAAs) to macrocyclic peptide drug discovery has origins in peptide natural products, specifically non-ribosomal peptides (NRPs) and ribosomally synthesized and post-translationally modified peptides (RiPPs) . Notable examples include cyclosporin A (an NRP) and, most recently, darobactin A (a RiPP), where biological activity can be attributed to multifaceted, unique AA architectures (Figure A) .…”