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PDBsum entry 2xr6
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Sugar binding protein
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PDB id
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2xr6
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References listed in PDB file
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Key reference
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Title
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Unique dc-Sign clustering activity of a small glycomimetic: a lesson for ligand design.
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Authors
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I.Sutkeviciute,
M.Thépaut,
S.Sattin,
A.Berzi,
J.Mcgeagh,
S.Grudinin,
J.Weiser,
A.Le roy,
J.J.Reina,
J.Rojo,
M.Clerici,
A.Bernardi,
C.Ebel,
F.Fieschi.
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Ref.
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Acs Chem Biol, 2014,
9,
1377-1385.
[DOI no: ]
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PubMed id
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Abstract
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DC-SIGN is a dendritic cell-specific C-type lectin receptor that recognizes
highly glycosylated ligands expressed on the surface of various pathogens. This
receptor plays an important role in the early stages of many viral infections,
including HIV, which makes it an interesting therapeutic target. Glycomimetic
compounds are good drug candidates for DC-SIGN inhibition due to their high
solubility, resistance to glycosidases, and nontoxicity. We studied the
structural properties of the interaction of the tetrameric DC-SIGN extracellular
domain (ECD), with two glycomimetic antagonists, a pseudomannobioside (1) and a
linear pseudomannotrioside (2). Though the inhibitory potency of 2, as measured
by SPR competition experiments, was 1 order of magnitude higher than that of 1,
crystal structures of the complexes within the DC-SIGN carbohydrate recognition
domain showed the same binding mode for both compounds. Moreover, when
conjugated to multivalent scaffolds, the inhibitory potencies of these compounds
became uniform. Combining isothermal titration microcalorimetry, analytical
ultracentrifugation, and dynamic light scattering techniques to study DC-SIGN
ECD interaction with these glycomimetics revealed that 2 is able, without any
multivalent presentation, to cluster DC-SIGN tetramers leading to an
artificially overestimated inhibitory potency. The use of multivalent scaffolds
presenting 1 or 2 in HIV trans-infection inhibition assay confirms the loss of
potency of 2 upon conjugation and the equal efficacy of chemically simpler
compound 1. This study documents a unique case where, among two active compounds
chemically derived, the compound with the lower apparent activity is the optimal
lead for further drug development.
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