Lanthipeptides: chemical synthesis versus in vivo biosynthesis as tools for pharmaceutical production

Abstract

Lanthipeptides (also called lantibiotics for those with antibacterial activities) are ribosomally synthesized post-translationally modified peptides having thioether cross-linked amino acids, lanthionines, as a structural element. Lanthipeptides have conceivable potentials to be used as therapeutics, however, the lack of stable, high-yield, well-characterized processes for their sustainable production limit their availability for clinical studies and further pharmaceutical commercialization. Though many reviews have discussed the various techniques that are currently employed to produce lanthipeptides, a direct comparison between these methods to assess industrial applicability has not yet been described. In this review we provide a synoptic comparison of research efforts on total synthesis and in vivo biosynthesis aimed at fostering lanthipeptides production. We further examine current applications and propose measures to enhance product yields. Owing to their elaborate chemical structures, chemical synthesis of these biomolecules is economically less feasible for large-scale applications, and hence biological production seems to be the only realistic alternative.

Bioorthogonal Metalloporphyrin‐Catalyzed Selective Methionine Alkylation in the Lanthipeptide Nisin

“…Nisin derivatives have been obtained by bio‐engineering . For modifications not accessible by bioengineering, site‐selective chemical modification of nisin is preferred, as its total synthesis is highly challenging …”

The next generation of antimicrobial peptides (AMPs) as molecular therapeutic tools for the treatment of diseases with social and economic impacts

“…Regardless of the method used, downstream processing is the crucial step before the commercialization of any peptide. This is the most expensive, time-consuming and testing phase of the production pipeline [55,56].…”

Bacteria Hunt Bacteria through an Intriguing Cyclic Peptide

“…They are rich in lanthionine or 3-methyllanthionine residues.T hese amino acids are synthesized posttranslationally inside the bacteria over two steps.F irst, dehydration of Ser or Thr takes place to yield the precursors 2,3-dehydroalanine (Dha) or 2,3-dehydrobutyrine (Dhb), which undergo Michael addition in the second step with the thiol of Cys to form lanthionine or 3-methyllanthionie (Schemes 5a nd 6). [84,[154][155][156] Lacticin 481 (15), [157,158] mutacin (16), [159,160] prochlorosin (17), [161,162] labyrinthopeptin A 2 (18), [163] and cinnamycin ( 19) [164] represent lantibiotics (Figure 7). All of these peptides are characterizedb yt he presenceo fc ross-linked lantionine.…”