DC-SIGN Antagonists – A Paradigm of C-Type Lectin Binding Inhibition

Anderluh, Marko

doi:10.5772/50627

Cited by 3 publications

(3 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All these compounds follow the same paradigm of glycomimetic design, where the "core monosaccharide" is utilized to selectively anchor the ligand in the lectin binding site, while the aglycon moiety attached to the anomeric center boosts the binding affinity. 29 Extensive efforts have been made not only to improve the affinity and selectivity of FimH antagonists, but also to ameliorate their pharmacokinetic properties. [23][24][25][26][27][28] In particular, biphenyl a-D-mannopyranoside derivatives were proven to offer excellent solubility as free acids, while ester prodrugs may be used to accomplish sufficient level of absorption, good 14 the latter rendered as a transparent surface coloured according to the electrostatic potential).…”

Section: Introductionmentioning

confidence: 99%

Branched α-d-mannopyranosides: a new class of potent FimH antagonists

et al. 2014

Self Cite

View full text Add to dashboard Cite

FimH is a type I fimbrial lectin located at the tip of type-1 pili of uropathogenic Escherichia coli guiding its ability to adhere and infect urothelial cells. Accordingly, blocking FimH with small-molecule antagonists is considered as a promising new therapeutic alternative to treat infections caused by uropathogenic Escherichia coli (UPEC). Herein we report that our recently disclosed a-D-mannopyranosides bearing diaryl substituted 1,3-diaminopropanol or glycerol moieties act as potent FimH antagonists in vitro, as determined by a competitive binding assay on isolated FimH lectin. Most of the assayed compounds display FimH antagonistic activity in the range of 58-1000 nM. Based on the promising results of the first series of compounds, we have designed and synthesized a new series of asymmetrically disubstituted glyceryl a-D-mannopyranosides with improved physicochemical properties. Molecular docking calculations were employed to predict compounds' binding poses leading to two possible binding modes; so-called in-and out-docking modes in the "tyrosine gate" (formed by Tyr48 and Tyr137) for one aromatic moiety, which is in accordance with previous findings, while the second aromatic moiety reaches the previously unexplored lipophilic region formed by Phe142 and Ile13. Furthermore, compounds were found to be non-cytotoxic on HepG2 cells in concentrations up to 10 mM pointing to their selective toxicity, which is one of the key features of potential therapeutics for the treatment of urinary tract infections.

show abstract

Section: Introductionmentioning

confidence: 99%

Branched α-d-mannopyranosides: a new class of potent FimH antagonists

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…In recent years studies devoted to the development of DC-SIGN therapeutic ligands have yielded new data in cell biology (203), immunology (204), and biochemistry (205, 206). The concept of therapeutic DC-SIGN antagonists/inhibitors is promising and in need of further development (9, 207). Targeting the MR is suggested for vaccine development (201), for delivery of cargo into macrophages (202) or liver cells (195).…”

Section: Discussionmentioning

confidence: 99%

Targeting the C-type Lectins-Mediated Host-Pathogen Interactions with Dextran

2014

View full text Add to dashboard Cite

Dextran, the α-1,6-linked glucose polymer widely used in biology and medicine, promises new applications. Linear dextran applied as a blood plasma substitute demonstrates a high rate of biocompatibility. Dextran is present in foods, drugs, and vaccines and in most cases is applied as a biologically inert substance. In this review we analyze dextran’s cellular uptake principles, receptor specificity and, therefore, its ability to interfere with pathogen–lectin interactions: a promising basis for new antimicrobial strategies. Dextran-binding receptors in humans include the DC-SIGN (dendritic cell–specific intercellular adhesion molecule 3-grabbing nonintegrin) family receptors: DC-SIGN (CD209) and L-SIGN (the liver and lymphatic endothelium homologue of DC-SIGN), the mannose receptor (CD206), and langerin. These receptors take part in the uptake of pathogens by dendritic cells and macrophages and may also participate in the modulation of immune responses, mostly shown to be beneficial for pathogens per se rather than host(s). It is logical to predict that owing to receptor-specific interactions, dextran or its derivatives can interfere with these immune responses and improve infection outcome. Recent data support this hypothesis. We consider dextran a promising molecule for the development of lectin–glycan interaction-blocking molecules (such as DC-SIGN inhibitors) that could be applied in the treatment of diseases including tuberculosis, influenza, hepatitis B and C, human immunodeficiency virus infection and AIDS, etc. Dextran derivatives indeed change the pathology of infections dependent on DC-SIGN and mannose receptors. Complete knowledge of specific dextran–lectin interactions may also be important for development of future dextran applications in biological research and medicine.

show abstract

“…In this study, to verify the predicted structure for the target molecule, protein–protein docking was used for the discovery of the receptor-ligand kinetics and responsible residues. According to the previously performed studies, l -fructose and d -mannose act as high-affinity ligands for the C-type lectin receptors [ 57 ]. Therefore, these molecules could be used as ligands for evaluating the lectin molecular interactions.…”

Section: Methodsmentioning

confidence: 99%

Developing a Vaccine to Block West Nile Virus Transmission: In Silico Studies, Molecular Characterization, Expression, and Blocking Activity of Culex pipiens mosGCTL-1

et al. 2021

View full text Add to dashboard Cite

Background: Mosquito galactose-specific C-type lectins (mosGCTLs), such as mosGCTL-1, act as ligands to facilitate the invasion of flaviviruses like West Nile virus (WNV). WNV interacts with the mosGCTL-1 of Aedes aegypti (Culicidae) and facilitates the invasion of this virus. Nevertheless, there is no data about the role of mosGCTL-1 as a transmission-blocking vaccine candidate in Culex pipiens, the most abundant Culicinae mosquito in temperate regions. Methods: Adult female Cx. pipiens mosquitoes were experimentally infected with a WNV infectious blood meal, and the effect of rabbit anti-rmosGCTL-1 antibodies on virus replication was evaluated. Additionally, in silico studies such as the prediction of protein structure, homology modeling, and molecular interactions were carried out. Results: We showed a 30% blocking activity of Cx. pipiens mosGCTL-1 polyclonal antibodies (compared to the 10% in the control group) with a decrease in infection rates in mosquitoes at day 5 post-infection, suggesting that there may be other proteins in the midgut of Cx. pipiens that could act as cooperative-receptors for WNV. In addition, docking results revealed that WNV binds with high affinity, to the Culex mosquito lectin receptors. Conclusions: Our results do not support the idea that mosGCTL-1 of Cx. pipiens primarily interacts with WNV to promote viral infection, suggesting that other mosGCTLs may act as primary infection factors in Cx. pipiens.

show abstract

DC-SIGN Antagonists – A Paradigm of C-Type Lectin Binding Inhibition

Cited by 3 publications

References 69 publications

Branched α-d-mannopyranosides: a new class of potent FimH antagonists

Branched α-d-mannopyranosides: a new class of potent FimH antagonists

Targeting the C-type Lectins-Mediated Host-Pathogen Interactions with Dextran

Developing a Vaccine to Block West Nile Virus Transmission: In Silico Studies, Molecular Characterization, Expression, and Blocking Activity of Culex pipiens mosGCTL-1

Contact Info

Product

Resources

About