We used the concept of chemical space to explore a virtual library of bicyclic peptides formed by double thioether cyclization of a precursor linear peptide, and identified an antimicrobial bicyclic peptide (AMBP) with remarkable activity against several MDR strains of Acinetobacter baumannii and Pseudomonas aeruginosa.
Herein we report X-ray crystal structures of 11-13 residue antimicrobial peptides (AMPs) active against Pseudomonas aeruginosa as complexes of fucosylated D-enantiomeric sequences with the P. aeruginosa lectin LecB. These represent the first crystal structures of short AMPs. In twenty-four individual structures of eight different peptides we found mostly α-helices assembled as two-helix or four-helix bundles with a hydrophobic core and cationic residues pointing outside. Two of the analogs formed an extended structure engaging in multiple contacts with the lectin. Molecular dynamics (MD) simulations showed that αhelices are stabilized by bundle formation and suggested that the N-terminal acyl group present in the linker to the fucosyl group can extend the helix by one additional H-bond and increase α-helix amphiphilicity. Investigating N-terminal acylation led to AMPs with equivalent and partly stronger antibacterial effects compared to the free peptide.
The peptide α-helix is right-handed when containing amino acids with L-chirality, and left-handed with D-chirality, however mixed chirality peptides generally do not form α-helices unless the non-natural residue amino-isobutyric acid...
This publication is dedicated to Prof. Philippe Renaud on the occasion of his 60 th Birthday Dendrimers are regularly branched molecular trees which are notoriously difficult to crystallize. Herein we report the crystal structure of a C-fucosylated second generation peptide dendrimer as complex with lectin LecB in which the only dendrimer-lectin contact is the LecB bound glycoside (PDB 6S5S). In contrast to a previously reported crystal structure of a first-generation peptide dendrimer as LecB complex in which the dendrimer formed trimers connected by intermolecular β-sheets (PDB 5D2A), the present structure features a globular monomeric state held together by intramolecular backbone hydrogen bonds and assembled into a non-covalent dimer stabilized by hydrophobic contacts between leucine side-chains and proline-phenylalanine CH-π stacking interactions. Molecular dynamics and circular dichroism studies suggest that this crystal structure resembles the structure of the peptide dendrimer in solution. Structures of a partially resolved dendrimer (PDB 6S5R) and of Cfucosylated disulfide bridged peptide dimers connecting different LecB tetramers are also reported (PDB 6S7G, PDB 6S5P). Scheme 1. Synthesis of peptide dendrimer SBD8. a) Standard Fmoc SPPS; b) i. Pd(PPh 3 ) 4 (0.25 equiv.), PhSiH 3 (25 equiv.), CH 2 Cl 2 , 2 × 45 min., ii. Standard Fmoc SPPS, iii. Peracetylated α-Lfucosyl-acetic acid/Oxyma/DIC in NMP/CH 2 Cl 2 , overnight; c) i. MeOH/H 2 O/NH 3 ·25 % aq. (8:1:1), 24 h, ii. CF 3 CO 2 H/ i Pr 3 SiH/H 2 O (95 : 2.5 : 2.5), 3.5 h.Figure 5. Backbone structure representation of peptide dendrimers SBD8 (X-ray structure), TNS18 and G3KL (MD models) with backbone H-bonds highlighted as dashed black lines.
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