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Talukdar A.,Purdue University | Morgunova E.,Karolinska Institutet | Duan J.,Anterio Consult and Research GmbH | Meining W.,TU Munich | And 7 more authors.
Bioorganic and Medicinal Chemistry

Virtual screening of a library of commercially available compounds versus the structure of Mycobacterium tuberculosis lumazine synthase identified 2-(2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)acetic acid (9) as a possible lead compound. Compound 9 proved to be an effective inhibitor of M. tuberculosis lumazine synthase with a Ki of 70 μM. Lead optimization through replacement of the carboxymethylsulfonamide sidechain with sulfonamides substituted with alkyl phosphates led to a four-carbon phosphate 38 that displayed a moderate increase in enzyme inhibitory activity (Ki 38 μM). Molecular modeling based on known lumazine synthase/inhibitor crystal structures suggests that the main forces stabilizing the present benzindolone/enzyme complexes involve π-π stacking interactions with Trp27 and hydrogen bonding of the phosphates with Arg128, the backbone nitrogens of Gly85 and Gln86, and the side chain hydroxyl of Thr87. © 2010 Elsevier Ltd. All rights reserved. Source

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: PEOPLE-2007-1-1-ITN | Award Amount: 3.12M | Year: 2009

The importance of glycosciences in the development of biology and medicine and the central role played by chemistry in this process have recently been pointed out by ESF. However, it appears that exposure of young scientists in their training phase to the chemical biology of carbohydrates is still lacking. This multidisciplinary project intends to approach the design and synthesis of carbohydrate multivalent systems to be used as tools to study the interaction between carbohydrates and DC-SIGN (Dendritic Cell-Specific ICAM-3 Grabbing Non-integrin), a C-type lectin implicated in the recognition of pathogens and in some of the earliest stages of the infection process. Targeting pathogens at the earliest stages of infection, before cell penetration, is of crucial importance because it can result in a significant decrease of pathogen titre in the organism and therefore will facilitate the efficiency of current therapies. The role that DC-SIGN plays in the immune response through the interaction and recognition of pathogens leads to a very complex pathway of signalling cascade that could be modulated using these carbohydrate multivalent systems as effectors. Thus the studies we propose could provide the background for the design, selection and preparation of better antiviral drugs and could afford new insights to unravel the complex mechanisms of the immune system, thus opening a strategy to develop vaccines through the modulation of dendritic cells activity. To reach these goals, a highly interdisciplinary group of scientists (synthetic chemists, computational chemists, biochemists, immunologists, etc.) has been assembled, some of whom are already collaborating on the topic. The planned flow of information between laboratories and the network-wide training activities described in this proposal will create an unrivalled environment for training of young scientists in glycosciences.

Andreini M.,University of Milan | Doknic D.,University of Milan | Sutkeviciute I.,CNRS Institute of Pharmacology and Structural Biology | Sutkeviciute I.,French National Center for Scientific Research | And 16 more authors.
Organic and Biomolecular Chemistry

DC-SIGN and Langerin are two C-type lectins involved in the initial steps of HIV infections: the former acts as a viral attachment factor and facilitates viral invasion of the immune system, the latter has a protective effect. Potential antiviral compounds targeted against DC-SIGN were synthesized using a common fucosylamide anchor. Their DC-SIGN affinity was tested by SPR and found to be similar to that of the natural ligand Lewis-X (Le X). The compounds were also found to be selective for DC-SIGN and to interact only weakly with Langerin. These molecules are potentially useful therapeutic tools against sexually transmitted HIV infection. © 2011 The Royal Society of Chemistry. Source

Sutkeviciute I.,CNRS Institute of Pharmacology and Structural Biology | Sutkeviciute I.,French National Center for Scientific Research | Sutkeviciute I.,CEA Grenoble | Thepaut M.,CNRS Institute of Pharmacology and Structural Biology | And 21 more authors.
ACS Chemical Biology

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. © 2014 American Chemical Society. Source

Varga N.,University of Milan | Sutkeviciute I.,CNRS Institute of Pharmacology and Structural Biology | Sutkeviciute I.,French National Center for Scientific Research | Sutkeviciute I.,CEA Grenoble | And 12 more authors.
Chemistry - A European Journal

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and Langerin are C-type lectins of dendritic cells (DCs) that share a specificity for mannose and are involved in pathogen recognition. HIV is known to use DC-SIGN on DCs to facilitate transinfection of T-cells. Langerin, on the contrary, contributes to virus elimination; therefore, the inhibition of this latter receptor is undesired. Glycomimetic molecules targeting DC-SIGN have been reported as promising agents for the inhibition of viral infections and for the modulation of immune responses mediated by DC-SIGN. We show here for the first time that glycomimetics based on a mannose anchor can be tuned to selectively inhibit DC-SIGN over Langerin. Based on structural and binding studies of a mannobioside mimic previously described by us (2), a focused library of derivatives was designed. The optimized synthesis gave fast and efficient access to a group of bis(amides), decorated with an azide-terminated tether allowing further conjugation. SPR inhibition tests showed improvements over the parent pseudomannobioside by a factor of 3-4. A dimeric, macrocyclic structure (11) was also serendipitously obtained, which afforded a 30-fold gain over the starting compound (2). The same ligands were tested against Langerin and found to exhibit high selectivity towards DC-SIGN. Structural studies using saturation transfer difference NMR spectroscopy (STD-NMR) were performed to analyze the binding mode of one representative library member with DC-SIGN. Despite the overlap of some signals, it was established that the new ligand interacts with the protein in the same fashion as the parent pseudodisaccharide. The two aromatic amide moieties showed relatively high saturation in the STD spectrum, which suggests that the improved potency of the bis(amides) over the parent dimethyl ester can be attributed to lipophilic interactions between the aromatic groups of the ligand and the binding site of DC-SIGN. Receptor targeting: For the first time glycomimetics based on a mannose anchor have been tuned to selectively inhibit DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) over Langerin. Based on structural and binding studies of a mannobioside mimic previously described, a focused library of derivatives was designed (see figure). Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

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