New lipophilic glycomimetic DC-SIGN ligands: Stereoselective synthesis and SPR-based binding inhibition assays

Autor: Mauro Pineschi, Paolo Crotti, Dalila Iacopini, Franck Fieschi, Vittorio Bordoni, Silvia Achilli, Valeria Di Bussolo, Michel Thépaut, Sebastiano Di Pietro
Přispěvatelé: Dipartimento di Farmacia, University of Pisa - Università di Pisa, Dipartimento Farm, Dipartimento di Chimica e Chimica Industriale, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Dipartimento Chim & Chim Ind, ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Rok vydání: 2021
Předmět:
Disaccharide
Mannose
Disaccharides
Ligands
01 natural sciences
Biochemistry
Fucose
chemistry.chemical_compound
Glycomimetic
MESH: Disaccharides
Drug Discovery
MESH: Ligands
Moiety
MESH: Receptors
Cell Surface
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
biology
Stereoisomerism
Stereoselectivity
Anti-Bacterial Agents
MESH: Surface Plasmon Resonance
DC-SIGN
MESH: Cell Adhesion Molecules
Anti-infective agents
Protein Binding
MESH: Antiviral Agents
Lipophilic interactions
Stereochemistry
Carbohydrates
Receptors
Cell Surface
Antiviral Agents
MESH: Anti-Bacterial Agents
Humans
MESH: Protein Binding
Lectins
C-Type
Molecular Biology
MESH: Humans
Bacteria
010405 organic chemistry
Ligand
Organic Chemistry
Surface Plasmon Resonance
MESH: Stereoisomerism
0104 chemical sciences
Glycomimetics
MESH: Bacteria
010404 medicinal & biomolecular chemistry
chemistry
biology.protein
Azide
Cell Adhesion Molecules
MESH: Lectins
C-Type
Zdroj: Bioorganic Chemistry
Bioorganic Chemistry, Elsevier, 2021, 107, pp.104566. ⟨10.1016/j.bioorg.2020.104566⟩
Bioorganic Chemistry, 2021, 107, pp.104566. ⟨10.1016/j.bioorg.2020.104566⟩
ISSN: 0045-2068
1090-2120
Popis: International audience; The design and synthesis of efficient ligands for DC-SIGN is a topic of high interest, because this C-type lectin has been implicated in the early stages of many infection processes. DC-SIGN membrane-protein presents four carbohydrate-binding domains (CRD) that specifically recognize mannose and fucose. Therefore, antagonists of minimal disaccharide epitope Manα(1,2)Man, represent potentially interesting antibacterial and antiviral agents. In the recent past, we were able to develop efficient antagonists, mimics of the natural moiety, characterized by the presence of a real d-carbamannose unit which confers greater stability to enzymatic breakdown than the corresponding natural disaccharide ligand. Herein, we present the challenging stereoselective synthesis of four new amino or azide glycomimetic DC-SIGN antagonists with attractive orthogonal lipophilic substituents in C(3), C(4) or C(6) positions of the real carba unit, which were expected to establish crucial interactions with lipophilic areas of DC-SIGN CRD. The activity of the new ligands was evaluated by SPR binding inhibition assays. The interesting results obtained, allow to acquire important information about the influence of the lipophilic substituents present in specific positions of the carba scaffold. Furthermore, C(6) benzyl C(4) tosylamide pseudodisaccharide displayed a good affinity for DC-SIGN with a more favorable IC50 value than those of the previously described real carba-analogues. This study provides valuable knowledge for the implementation of further structural modifications towards improved inhibitors.
Databáze: OpenAIRE
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