315 research outputs found
OA011-03. Clusterin, a natural ligand of DC-SIGN present in human semen inhibits HIV capture and transmission by dendritic cells
International audiencen.
Design and synthesis of inhibitors of DC-sign mediated infections
DC-SIGN (Dendritic Cell-Specific ICAM-3 Grabbing Nonintegrin) is a C-type (Calcium dependent) lectin, expressed as homotetramers (presenting four copies of a Carbohydrate Recognition Domain (CRD) at the C-terminus) on the surface of immature Dendritic Cells. [1]
Dendritic Cells (DCs) areone of the most important class of Antigen Presenting Cells (APCs). They recognize many pathogens through various receptors such as DC-SIGN. After recognition, the pathogen is internalized and DCs mature and migrate to lymph nodes.[2] Then, DCs relay the corresponding processing antigens as MHC complexes to naive T-cells, which differentiate allowing the appropriate immuno-reponse. Some of these pathogens, such as HIV, hijack this mechanism to infect the immune system: they are recognized by DCs but escape the processing pathway. Thus, they can remain âhiddenâ inside the dendritic cells for many days, being able to reach and infect their target T-cells.
The main carbohydrate ligand recognized by DC-SIGN is the high mannose glycan (Man)9(GlcNAc)2 , also known as Man9, a branched oligosaccharide which is presented in multiple copies by several pathogen glycoproteins (gp120, GP1, âŠ). Hence, multivalent mannose display should be an adequate strategy to interact with this lectin with high affinity.
In vivo, mannosides are normally hydrolyzed by mannosidases: the use of a structural mimic in place of the natural sugar could avoid an easy degradation in a biological environment. The aim of this project is to design and prepare products that meet these requirements.
So far we have demonstrated that the monovalent mimic 1 shown in Figure 1[3] interacts with DC-SIGN (using NMR) and inhibits the DC-SIGN mediated infection in a pseudo-typed Ebola virus model.
Moreover, this molecule has been conjugated to a Boltorn-type, leading to neo-glycoconjugates that inhibit the binding of DC-SIGN to gp120 (envelope protein of HIV).
In this communication we will report the synthesis of new monovalent inhibitors and the results of their binding assays by SPR. We will show also the synthesis of some multivalent compounds.
Acknowledgments. This work was supported by Azioni Integrate Italia-Spagna (IT074ABCCM).
[1] T. B. H. Geijtenbeek, , Y. van Kook, et al., Cell 2000, 100, 575-585.
[2] Y. van Kooyk, T. B. H. Geijtenbeek, Nat. Rev. Immunol. 2003, 3, 697-709.
[3] JosĂ© J. Reina, Sara Sattin, Donatella Invernizzi, Silvia Mari, Lorena MartĂnez-Prats, Georges Tabarani, Franck Fieschi, Rafael Delgado, Pedro M. Nieto, Javier Rojo, Anna Bernardi, ChemMedChem , 2007, 2(7),1030-1036
Detection and Quantitative Analysis of Two Independent Binding Modes of a Small Ligand Responsible for DC-SIGN Clustering
DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) is a C-type lectin receptor (CLRs) present, mainly in dendritic cells (DCs), as one of the major pattern recognition receptors (PRRs). This receptor has a relevant role in viral infection processes. Recent approaches aiming to block DC-SIGN have been presented as attractive anti-HIV strategies. DC-SIGN binds mannose or fucose-containing carbohydrates from viral proteins such as the HIV envelope glycoprotein gp120. We have previously demonstrated that multivalent dendrons bearing multiple copies of glycomimetic ligands were able to inhibit DC-SIGN-dependent HIV infection in cervical explant models. Optimization of glycomimetic ligands requires detailed characterization and analysis of their binding modes because they notably influence binding affinities. In a previous study we characterized the binding mode of DC-SIGN with ligand 1, which shows a single binding mode as demonstrated by NMR and X-ray crystallography. In this work we report the binding studies of DC-SIGN with pseudotrisaccharide 2, which has a larger affinity. Their binding was analysed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol and molecular modelling. These studies demonstrate that in solution the complex cannot be explained by a single binding mode. We describe the ensemble of ligand bound modes that best fit the experimental data and explain the higher inhibition values found for ligand
Exclusive Neutral Pion Electroproduction in the Deeply Virtual Regime
We present measurements of the ep->ep pi^0 cross section extracted at two
values of four-momentum transfer Q^2=1.9 GeV^2 and Q^2=2.3 GeV^2 at Jefferson
Lab Hall A. The kinematic range allows to study the evolution of the extracted
hadronic tensor as a function of Q^2 and W. Results will be confronted with
Regge inspired calculations and GPD predictions. An intepretation of our data
within the framework of semi-inclusive deep inelastic scattering has also been
attempted
Scaling Tests of the Cross Section for Deeply Virtual Compton Scattering
We present the first measurements of the \vec{e}p->epg cross section in the
deeply virtual Compton scattering (DVCS) regime and the valence quark region.
The Q^2 dependence (from 1.5 to 2.3 GeV^2) of the helicity-dependent cross
section indicates the twist-2 dominance of DVCS, proving that generalized
parton distributions (GPDs) are accessible to experiment at moderate Q^2. The
helicity-independent cross section is also measured at Q^2=2.3 GeV^2. We
present the first model-independent measurement of linear combinations of GPDs
and GPD integrals up to the twist-3 approximation.Comment: 5 pages, 4 figures, 2 tables. Text shortened for publication.
References added. One figure remove
Deeply Virtual Compton Scattering off the neutron
The present experiment exploits the interference between the Deeply Virtual
Compton Scattering (DVCS) and the Bethe-Heitler processes to extract the
imaginary part of DVCS amplitudes on the neutron and on the deuteron from the
helicity-dependent D cross section measured at =1.9
GeV and =0.36. We extract a linear combination of generalized parton
distributions (GPDs) particularly sensitive to , the least constrained
GPD. A model dependent constraint on the contribution of the up and down quarks
to the nucleon spin is deduced.Comment: Published in Phys. Rev. Let
The E00-110 experiment in Jefferson Lab's Hall A: Deeply Virtual Compton Scattering off the Proton at 6 GeV
We present final results on the photon electroproduction
() cross section in the deeply virtual Compton
scattering (DVCS) regime and the valence quark region from Jefferson Lab
experiment E00-110. Results from an analysis of a subset of these data were
published before, but the analysis has been improved which is described here at
length, together with details on the experimental setup. Furthermore,
additional data have been analyzed resulting in photon electroproduction cross
sections at new kinematic settings, for a total of 588 experimental bins.
Results of the - and -dependences of both the helicity-dependent and
helicity-independent cross sections are discussed. The -dependence
illustrates the dominance of the twist-2 handbag amplitude in the kinematics of
the experiment, as previously noted. Thanks to the excellent accuracy of this
high luminosity experiment, it becomes clear that the unpolarized cross section
shows a significant deviation from the Bethe-Heitler process in our kinematics,
compatible with a large contribution from the leading twist-2 DVCS term to
the photon electroproduction cross section. The necessity to include
higher-twist corrections in order to fully reproduce the shape of the data is
also discussed. The DVCS cross sections in this paper represent the final set
of experimental results from E00-110, superseding the previous publication.Comment: 48 pages, 32 figure
Internet-based medical education: a realist review of what works, for whom and in what circumstances
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