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PDBsum entry 4lkd
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Sugar binding protein/inhibitor
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PDB id
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4lkd
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References listed in PDB file
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Key reference
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Title
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Structure-Based optimization of the terminal tripeptide in glycopeptide dendrimer inhibitors of pseudomonas aeruginosa biofilms targeting leca.
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Authors
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R.U.Kadam,
M.Bergmann,
D.Garg,
G.Gabrieli,
A.Stocker,
T.Darbre,
J.L.Reymond.
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Ref.
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Chemistry, 2013,
19,
17054-17063.
[DOI no: ]
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PubMed id
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Abstract
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The galactopeptide dendrimer GalAG2
((β-Gal-OC6H4CO-Lys-Pro-Leu)4(Lys-Phe-Lys-Ile)2Lys-His-Ile-NH2) binds strongly
to the Pseudomonas aeruginosa (PA) lectin LecA, and it inhibits PA biofilms, as
well as disperses already established ones. By starting with the crystal
structure of the terminal tripeptide moiety GalA-KPL in complex with LecA, a
computational mutagenesis study was carried out on the galactotripeptide to
optimize the peptide-lectin interactions. 25 mutants were experimentally
evaluated by a hemagglutination inhibition assay, 17 by isothermal titration
calorimetry, and 3 by X-ray crystallography. Two of these tripeptides, GalA-KPY
(dissociation constant (K(D))=2.7 μM) and GalA-KRL (K(D)=2.7 μM), are among
the most potent monovalent LecA ligands reported to date. Dendrimers based on
these tripeptide ligands showed improved PA biofilm inhibition and dispersal
compared to those of GalAG2, particularly G2KPY
((β-Gal-OC6H4CO-Lys-Pro-Tyr)4(Lys-Phe-Lys-Ile)2Lys-His-Ile-NH2). The
possibility to retain and even improve the biofilm inhibition in several
analogues of GalAG2 suggests that it should be possible to fine-tune this
dendrimer towards therapeutic use by adjusting the pharmacokinetic parameters in
addition to the biofilm inhibition through amino acid substitutions.
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