Unique DC-SIGN clustering activity of a small glycomimetic

A lesson for ligand design

Ieva Sutkeviciute, Michel Thépaut, Sara Sattin, Angela Berzi, John McGeagh, Sergei Grudinin, Jorg Weiser, Aline Le Roy, Jose J. Reina, Javier Rojo, Mario Clerici, Anna Bernardi, Christine Ebel, Franck Fieschi

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1377-1385
Number of pages9
JournalACS Chemical Biology
Volume9
Issue number6
DOIs
Publication statusPublished - Jun 20 2014

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Cluster Analysis
Ligands
Scaffolds
C-Type Lectins
Glycoside Hydrolases
Ultracentrifugation
Pathogens
Virus Diseases
Dynamic light scattering
Titration
Pharmaceutical Preparations
Solubility
Dendritic Cells
HIV Infections
DC-specific ICAM-3 grabbing nonintegrin
Structural properties
Assays
Crystal structure
Carbohydrates
HIV

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Medicine(all)

Cite this

Sutkeviciute, I., Thépaut, M., Sattin, S., Berzi, A., McGeagh, J., Grudinin, S., ... Fieschi, F. (2014). Unique DC-SIGN clustering activity of a small glycomimetic: A lesson for ligand design. ACS Chemical Biology, 9(6), 1377-1385. https://doi.org/10.1021/cb500054h

Unique DC-SIGN clustering activity of a small glycomimetic : A lesson for ligand design. / Sutkeviciute, Ieva; Thépaut, Michel; Sattin, Sara; Berzi, Angela; McGeagh, John; Grudinin, Sergei; Weiser, Jorg; Le Roy, Aline; Reina, Jose J.; Rojo, Javier; Clerici, Mario; Bernardi, Anna; Ebel, Christine; Fieschi, Franck.

In: ACS Chemical Biology, Vol. 9, No. 6, 20.06.2014, p. 1377-1385.

Research output: Contribution to journalArticle

Sutkeviciute, I, Thépaut, M, Sattin, S, Berzi, A, McGeagh, J, Grudinin, S, Weiser, J, Le Roy, A, Reina, JJ, Rojo, J, Clerici, M, Bernardi, A, Ebel, C & Fieschi, F 2014, 'Unique DC-SIGN clustering activity of a small glycomimetic: A lesson for ligand design', ACS Chemical Biology, vol. 9, no. 6, pp. 1377-1385. https://doi.org/10.1021/cb500054h
Sutkeviciute I, Thépaut M, Sattin S, Berzi A, McGeagh J, Grudinin S et al. Unique DC-SIGN clustering activity of a small glycomimetic: A lesson for ligand design. ACS Chemical Biology. 2014 Jun 20;9(6):1377-1385. https://doi.org/10.1021/cb500054h
Sutkeviciute, Ieva ; Thépaut, Michel ; Sattin, Sara ; Berzi, Angela ; McGeagh, John ; Grudinin, Sergei ; Weiser, Jorg ; Le Roy, Aline ; Reina, Jose J. ; Rojo, Javier ; Clerici, Mario ; Bernardi, Anna ; Ebel, Christine ; Fieschi, Franck. / Unique DC-SIGN clustering activity of a small glycomimetic : A lesson for ligand design. In: ACS Chemical Biology. 2014 ; Vol. 9, No. 6. pp. 1377-1385.
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