An antimicrobial bicyclic peptide from chemical space against multidrug resistant Gram-negative bacteria

Bonaventura, Ivan Di; Baeriswyl, S.; Capecchi, Alice; Gan, Bee‐Ha; Jin, Xian; Siriwardena, Thissa N.; He, Runze; Köhler, Thilo; Pompilio, Arianna; Bonaventura, Giovanni Di; Delden, Christian van; Javor, Sacha; Reymond, Jean‐Louis

doi:10.1039/c8cc02412j

Cited by 31 publications

(51 citation statements)

References 43 publications

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“…We also additionally optimized G3KL using a chemical space exploration method initially demonstrated for bicyclic peptides to test sequence variations that were not accessible by combinatorial chemistry. [35,36] This approach led to the discovery of AMPD T7, a close analog of G3KL in which the two G1 dipeptides have been extended to lysine-leucine-leucine (KLL) tripeptides and the G0 core to a lysinelysine-leucine (KKL) tripeptide. [37] These seemingly minor modifications conferred additional activity to T7 against Klebsiella pneumoniae strains for which neither G3KL nor TNS18 showed any activity.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial Peptide Dendrimer Chimera

Siriwardena

Lüscher

Köhler

et al. 2019

Helvetica Chimica Acta

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We recently reported the discovery of antimicrobial peptide dendrimers (AMPDs) acting by a membrane‐disruptive mechanism against multidrug resistant pathogenic bacteria. Here, we combined amino acid sequence elements from different AMPDs with different activity profiles to form AMPD chimeras. By joining the outer branches of TNS18, an AMPD active against Pseudomonas aeruginosa, Acinetobacter baumannii and methicillin resistant Staphylococcus aureus, with the core of T7, another AMPD active against P. aeruginosa, A. baumannii and Klebsiella pneumoniae, we obtained AMPD chimera DC5 displaying all previously observed activities while retaining a similar mechanism of action. These experiments show that chimera design represents a useful strategy to improve the properties of AMPDs.

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Section: Introductionmentioning

confidence: 99%

Antimicrobial Peptide Dendrimer Chimera

Siriwardena

Lüscher

Köhler

et al. 2019

Helvetica Chimica Acta

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“…MXFP is a 217D atom pair topological distance fingerprint calculated using an in-house Java program in a similar manner to our previously reported atom pair fingerprints 3DP and 2DP tailored for peptides and proteins. [19][20] Topological distances are measured using the TopologyAna-lyzerPlugin provided as part of the JChem library by ChemAxon. There are seven atom categories: heavy atom (HA), hydrophobic (HY), aromatic atoms (AR), hydrogen bond acceptor and donor (HBA, HBD), positively charged (POS) and negatively charged (NEG), and only samecategory atom pairs are considered.…”

Section: Fingerprint Calculationmentioning

confidence: 99%

“…MXFP is a 217D fingerprint counting atom-pairs using a fuzzy approach to assign atom-pairs to distance bins as done previously in our analysis of proteins and peptides. [19][20] In the case of proteins, we used an atom-pair fingerprint called 3DP which considers through-space distances between atoms in experimental 3D-structures from the Protein Databank. [19] To analyze peptides, we adapted our approach to use topological distances between residues in a related fingerprint called 2DP, with all atoms in a residue positioned at the a-carbon atom.…”

Section: Macromolecule Extended Atom-pair Fingerprint Mxfpmentioning

confidence: 99%

“…Furthermore, we have already used atom pair fingerprints successfully to describe large molecules, in one case for detailed comparisons of 3Dmodels of biomacromolecules such as proteins and nucleic acids in the Protein DataBank (PDB), [19] and in the second case to perform virtual screening in libraries of peptide dendrimers and bicyclic peptides. [20] In the latter case our atom-pair fingerprint analysis perceives meaningful differences between peptides of identical composition but different sequences.…”

Section: Introductionmentioning

confidence: 95%

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PubChem and ChEMBL beyond Lipinski

Capecchi

Awale

Probst

et al. 2019

Molecular Informatics

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Seven million of the currently 94 million entries in the PubChem database break at least one of the four Lipinski constraints for oral bioavailability, 183,185 of which are also found in the ChEMBL database. These non‐Lipinski PubChem (NLP) and ChEMBL (NLC) subsets are interesting because they contain new modalities that can display biological properties not accessible to small molecule drugs. Unfortunately, the current search tools in PubChem and ChEMBL are designed for small molecules and are not well suited to explore these subsets, which therefore remain poorly appreciated. Herein we report MXFP (macromolecule extended atom‐pair fingerprint), a 217‐D fingerprint tailored to analyze large molecules in terms of molecular shape and pharmacophores. We implement MXFP in two web‐based applications, the first one to visualize NLP and NLC interactively using Faerun (http://faerun.gdb.tools/), the second one to perform MXFP nearest neighbor searches in NLP and NLC (http://similaritysearch.gdb.tools/). We show that these tools provide a meaningful insight into the diversity of large molecules in NLP and NLC. The interactive tools presented here are publicly available at http://gdb.unibe.ch and can be used freely to explore and better understand the diversity of non‐Lipinski molecules in PubChem and ChEMBL.

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“…The X‐ray crystal structure presented herein features a fucosylated dendrimer in complex with the fucose specific Pseudomonas aeruginosa lectin LecB . LecB mediated crystallography is very useful to elucidate the structure of molecules otherwise difficult to crystallize such as oligonucleotides, cyclic, bicyclic, and linear peptides . We focused on this approach because we had previously collected promising crystallographic data with dendrimer lectin complexes.…”

Section: Introductionmentioning

confidence: 99%

X‐Ray Crystal Structure of a Second‐Generation Peptide Dendrimer in Complex with Pseudomonas aeruginosa Lectin LecB

Baeriswyl

Javor

Stocker

et al. 2019

Helvetica Chimica Acta

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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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An antimicrobial bicyclic peptide from chemical space against multidrug resistant Gram-negative bacteria

Cited by 31 publications

References 43 publications

Antimicrobial Peptide Dendrimer Chimera

Antimicrobial Peptide Dendrimer Chimera

PubChem and ChEMBL beyond Lipinski

X‐Ray Crystal Structure of a Second‐Generation Peptide Dendrimer in Complex with Pseudomonas aeruginosa Lectin LecB

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