Discovery of Biologically Optimized Polymyxin Derivatives Facilitated by Peptide Scanning and In Situ Screening Chemistry

Abstract

Peptides can be converted to highly active compounds by introducing appropriate substituents on the suitable amino acid residue. Although modifiable residues in peptides can be systematically identified by peptide scanning methodologies, there is no practical method for optimization at the "scanned" position. With the purpose of using derivatives not only for scanning but also as a starting point for further chemical functionalization, we herein report the "scanning and direct derivatization" strategy through chemoselective acylation of embedded threonine residues by a serine/threonine ligation (STL) with the help of in situ screening chemistry. We have applied this strategy to the optimization of the polymyxin antibiotics, which were selected as a model system to highlight the power of the rapid derivatization of active scanning derivatives. Using this approach, we explored the structure−activity relationships of the polymyxins and successfully prepared derivatives with activity against polymyxin-resistant bacteria and those with Pseudomonas aeruginosa selective antibacterial activity. This strategy opens up efficient structural exploration and further optimization of peptide sequences.

Molecular Crowding Alters the Interactions of Polymyxin Lipopeptides within the Periplasm of E. coli: Insights from Molecular Dynamics

“…However, our simulations have certainly highlighted that the patterns and modes of interaction of lipoprotein antibiotics with the cell wall and proteins within the periplasm are impacted by the nature of the other species present in the vicinity. The search for polymyxin derivatives is an active area, 65 and it is our contention that a more nuanced consideration of the local environment may be beneficial for this end and, indeed, more generally for the future design of antibiotics that negotiate the periplasm to either act on the inner membrane or penetrate beyond the inner membrane into the cytoplasm.…”

Electrosynthesis of Artificial Peptides and Nucleosides via the Nitromethane–Lithium Perchlorate Electrolyte System: A Review

“…Artificial peptides with non-natural amino acid building blocks are frequently applied as pharmaceutical agents because they often exhibit superior pharmacological properties (e. g., higher bioavailability and increased affinity with target molecules) compared with natural peptides. [37,38] Particularly, proline residues are often considered the core structure in peptidomimetics because they govern the three-dimensional architecture of polypeptides due to conformational rigidity derived from the high rotational barrier on the N-acyl moiety and the restricted cyclic structure (Figure 3). [39,40] In proline-based peptidomimetics, the CÀ H bond of pyrrolidine is a more suitable modification site than the N-or Cterminus because substituents on the pyrrolidine skeleton had no influence on further peptide elongation from the proline residue.…”

Nanomole‐scale photochemical thiol‐ene chemistry for high‐throughput late‐stage diversification of peptide macrocycles

“…Additionally, the use of serine/threonine ligation was recently reported for similar applications, though this of course necessitates either a serine or threonine residue with a free amine. [ 11 ] Further, both of the aforementioned methodologies introduce additional polar groups, which may hamper membrane permeability of any lead compounds produced. As such, we sought to use chemoselective radical‐mediated processes in the form of the photochemical thiol‐ene reaction.…”