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dc.creatorSutkeviciute, Ievaes
dc.creatorThépaut, Micheles
dc.creatorSattin, Saraes
dc.creatorBerzi, Angelaes
dc.creatorMcGeagh, Johnes
dc.creatorGrudinin, Sergeies
dc.creatorWeiser, Jöerges
dc.creatorLe Roy, Alinees
dc.creatorReina, José J.es
dc.creatorRojo, Javieres
dc.creatorClerici, Marioes
dc.creatorBernardi, Annaes
dc.date.accessioned2018-01-29T15:01:27Z
dc.date.available2018-01-29T15:01:27Z
dc.date.issued2014
dc.identifier.citationSutkeviciute, I., Thépaut, M., Sattin, S., Berzi, A., McGeagh, J., Grudinin, S.,...,Bernardi, A. (2014). Unique DC-SIGN clustering activity of a small glycomimetic: a lesson for ligand design. ACS Chemical Biology, 9 (6), 1377-1385.
dc.identifier.issn1554-8929 (impreso)es
dc.identifier.issn1554-8937 (electrónico)es
dc.identifier.urihttps://hdl.handle.net/11441/69681
dc.description.abstractDC-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 developmentes
dc.description.sponsorshipEuropean Commission Marie Curie ITN FP7 PITN-GA-2008-213592es
dc.description.sponsorshipAgence Nationale de la Recherche ANR-11-MONU-006-01es
dc.formatapplication/pdfes
dc.language.isoenges
dc.publisherAmerican Chemical Societyes
dc.relation.ispartofACS Chemical Biology, 9 (6), 1377-1385.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectC-Type Lectines
dc.subjectHIVes
dc.subjectGlycomimeticses
dc.subjectClusteringes
dc.subjectAnalytical ultracentrifugationes
dc.subjectIsothermal microcalorimetryes
dc.titleUnique DC-SIGN clustering activity of a small glycomimetic: a lesson for ligand designes
dc.typeinfo:eu-repo/semantics/articlees
dcterms.identifierhttps://ror.org/03yxnpp24
dc.type.versioninfo:eu-repo/semantics/submittedVersiones
dc.rights.accessrightsinfo:eu-repo/semantics/openAccesses
dc.relation.projectIDPITN-GA-2008-213592es
dc.relation.projectIDANR-11-MONU-006-01es
dc.relation.publisherversionhttp://dx.doi.org/10.1021/cb500054hes
dc.identifier.doi10.1021/cb500054hes
idus.format.extent23 p.es
dc.journaltitleACS Chemical Biologyes
dc.publication.volumen9es
dc.publication.issue6es
dc.publication.initialPage1377es
dc.publication.endPage1385es
dc.contributor.funderEuropean Commission (EC)
dc.contributor.funderAgence Nationale de la Recherche. France

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