Iterative Antimicrobial Candidate Selection from Informed D‐/L‐Peptide Dimer Libraries

Abstract

Growing resistance to antibiotics, as well as newly emerging pathogens, stimulate the investigation of antimicrobial peptides (AMPs) as therapeutic agents. Here, we report a new library design concept based on a stochastic distribution of natural AMP amino acid sequences onto half-length synthetic peptides. For these compounds, a non-natural motif of alternating D- and L-backbone stereochemistry of the peptide chain predisposed for β-helix formation was explored. Synthetic D-/L-peptides with permuted half-length sequences were delineated from a full-length starter sequence and covalently recombined to create two-dimensional compound arrays for antibacterial screening. Using the natural AMP magainin as a seed sequence, we identified and iteratively optimized hit compounds showing high antimicrobial activity against Gram-positive and Gram-negative bacteria with low hemolytic activity. Cryo-electron microscopy characterized the membrane-associated mechanism of action of the new D-/L-peptide antibiotics.

Lipidated Peptide Dendrimers Killing Multidrug-Resistant Bacteria

“…[4][5][6][7][8] These designed analogs are expected to overcome the typical limitations of peptides in terms of stability. Most reports to date exploited classical linear or cyclic chain topologies while introducing alternative building blocks such as D-enantiomeric [9][10][11][12] and βamino acids, 13 peptoids, [14][15][16][17][18][19][20] nylon, 21,22 or urea linked diamines. 23,24 In our approach by contrast, we explore unusual multibranched topologies of the peptide chain, such as peptide dendrimers and bicyclic peptides, while keeping building blocks constant.…”

Dynamic Combinatorial Enrichment of Polyconformational D‐/L‐Peptide Dimers

“…Specifically,a9-fluorenylmethoxycarbonyl (Fmoc) strategy on a4 -OMe-tritylchloride resin preloadedw ith 2-aminoethanethiol or at ritylchloride resin preloaded with 2-aminoethanol, respectively,w ereu sed (Scheme 2). [20] The crude products were purified by preparative reversed-phase (RP) HPLC and characterizedb yM ALDI-MS and NMR spectroscopy (see the Supporting Information). The DCLs generated from these gA thiols were analyzed by comparison of the library members with the possible topologically constrained parallel and antiparallel disulfide dimers.…”

“…The gA thiol derivatives 2 and 3 were directly assembled by solid‐phase peptide synthesis (SPPS). Specifically, a 9‐fluorenylmethoxycarbonyl (Fmoc) strategy on a 4‐OMe‐tritylchloride resin preloaded with 2‐aminoethanethiol or a tritylchloride resin preloaded with 2‐aminoethanol, respectively, were used (Scheme ) 20. The crude products were purified by preparative reversed‐phase (RP) HPLC and characterized by MALDI‐MS and NMR spectroscopy (see the Supporting Information).…”

Strukturaufklärung und Aktivität des aus einer riesigen nicht‐ ribosomalen Peptidsynthetase stammenden D‐/L‐Pentadecapeptids Kolossin A

“…[23] Die Peptide wurde unter Nutzung eines Peptidsyntheseautomatenvom C-zum N-Terminus hin aufgebaut (Schema 1). Umfangreiche,v on Präzedenz mit schwierigen lipophilen d-/l-Peptiden ausgehende Experimente [24,25] führten zu einer optimierten Synthesevorschrift, die aus Kupplungszyklen beschleunigter Fmoc-Entschützungen, HBTU-vermittelter Kupplungen in DMF und systematischen "Cappings" bestand (Schema 1). Die Ausgangsbeladung des Harzes 13 betrug 0.4 mmol g À1 .K onventionelle Nterminale Formylierung voll entschützter d-/l-Peptide in Lçsung oder mithilfe von Standardreagentien [26] am Harzgebundenen Peptid führte zu unreinen Produkten, offensichtlich wegen mangelnder Chemoselektivität und schwieriger Abtrennung von Nebenprodukten.…”