1,721,012 research outputs found
Mannose-based glycomimetics acting as selective ligands for L-SIGN
Full text linkDC-SIGN and L-SIGN – also referred to as Dendritic Cell-Specific Intracellular Adhesion molecules (ICAM)-3 Grabbing Non-integrin (CD209) and Liver/Lymphnode-Specific ICAM-3 Grabbing Non-integrin (CD209L), respectively – are two C-type lectin receptors (CLRs), sharing 77% of their amino acidic sequences.1 They are able to bind to glycan motifs directly expressed at the surface of different pathogens thanks to a Ca2+ ion in the binding site – the so-called Carbohydrate Receptor Domain (CRD) – suddenly inducing the activation of the initial stages of adaptive immune response.
Nevertheless, several deadly viruses – such as HIV, Ebola, hepatitis C viruses, Dengue and West Nile virus – have developed strategies to subvert the function of CLRs to escape antiviral immunity and promote infection.2 Beyond the cited microorganisms, DC-SIGN and L-SIGN have been recently found to be entry co-factors for SARS-CoV-2, promoting trans-infection of ACE2-expressing cells.3
Interestingly, while fundamental studies have been performed in last years to design and characterize molecules acting as inhibitors of DC-SIGN-mediated infections, the first set of mannose-based ligands for L-SIGN was reported by our group only in 2022.4 According to this paper, the tested glycomimetics could inhibit the interaction of both lectins with the SARS-CoV-2 spike glycoprotein in a Surface Plasmon Resonance (SPR) assay and are more potent than mannose by up to 36-fold (DC-SIGN) and 10-fold (L-SIGN).
In this context, we present a new set of mannose-based glycomimetics which could selectively inhibit L-SIGN against DC-SIGN. All the molecules are based on a mono-mannose scaffold, modified at position 2 with a triazole moiety
Man-based glycomimetics inhibit DC/L-SIGN interaction with SARS-CoV-2 spike protein
No full textDC-SIGN and its homologue L-SIGN are two tetrameric transmembrane C-type lectins that share 77% of their amino-acidic sequence. Despite their high similarity, some important differences are present: DC-SIGN is expressed by immature dendritic cells located on dermal and mucosal tissues and can recognize both mannosylated and fucosylated structures; while L-SIGN expression is limited to specific tissues (e.g. lungs, liver and lymph-nodes) and preferentially binds mannose-containing carbohydrates.
They are well known receptor for glycosylated pathogens (e.g. HIV-1, Ebola, Dengue) and were recently identified as entry co-factors for SARS-CoV-2. Since L-SIGN is co-expressed with ACE2 on respiratory tract cells, the need for potent and selective antagonist is real and urgent.
Over the past decades, several efforts have been made for the development of DC-SIGN ligands as inhibitors of DC-SIGN mediated infections; however, no ligands have been reported so far to bind to L-SIGN.
Here, we present the first set of mannose-based glycomimetic ligands which bind to L-SIGN in an SPR inhibition experiment showing that they inhibit binding of both DC-SIGN and L-SIGN to immobilized SARS-CoV-2 spike protein.
All the ligands examined present a mannose residue modified at position 2 with a triazole moiety, both as a part of a pseudo-dimannoside or as a monosaccharide.
The design, synthesis and activity evaluation of the ligands will be discussed
C2-Triazole-modified mannose-based L-SIGN antagonists
No full textL-SIGN - Liver/lymph node-specific ICAM-3-grabbing integrin – is a tetrameric transmembrane C-type lectin, which shares 77% amino acid sequence with DC-SIGN and displays similar activity for highly mannosylated oligosaccharides. It is expressed in human lungs in type II alveolar cells and in endothelial cells and has recently been characterized as an entry co-factor for SARS-CoV-2.
Over the past decades, important efforts have been made for the development of DC-SIGN ligands as inhibitors of DC-SIGN mediated infections; however, no ligands have been reported so far to bind to L-SIGN.
Here, we present the first set of mannose-based glycomimetic ligands which bind to L-SIGN in an SPR inhibition experiment showing that they inhibit binding of both DC-SIGN and L-SIGN to immobilized SARS-CoV-2 spike protein.
All the ligands examined present a mannose residue modified at position 2 with a triazole moiety, both as a part of a pseudo-dimannoside or as a monosaccharide. The design, synthesis and activity evaluation of the ligands will be discussed
Multivalent DC-SIGN Ligands With a Rigid Core of Controlled Length
No full textHuman immunodeficiency virus (HIV) is still a huge health problem, causing the death of over 1
million people per year. The search for HIV-entry inhibitors represents a promising challenge to prevent HIV infection. In this field, DC-SIGN, a receptor expressed at the surface of the mucosal dendritic cells and involved in the early stages of HIV infection, is an important cellular target.1
DC-SIGN is a calcium-dependant tetrameric lectin, which recognizes and binds high-mannose
oligosaccharides displayed at the surface of HIV virus. The use of artificial molecules displaying
multivalent carbohydrate moieties, able to interact with DC-SIGN with good affinity, should represent a therapeutic strategy in order to prevent HIV attachment to dendritic cells.
Here we present a library of multivalent glycomimetic compounds potentially able to bind
simultaneously two binding sites on DC-SIGN, thus exploiting the chelating binding mode to enhance their affinity for the target. Compounds were synthesised by varying the length of a rigid aromatic scaffold and the nature as well as the valency of the sugar moieties at each end of the central core.
Every synthesised compound has been tested as HIV inhibitor through Surface Plasmon
Resonance (SPR) inhibition assays.
Some of the synthesised compounds were tested for the ability to inhibit HIV transmission in an in
vitro trans infection assay, revealing a high activity that seems depend on scaffold length. Tests were performed by Dr. Angela Berzi, in the laboratories of Prof. Mario Clerici (University of Milan).
Synthetic pathways and biological tests will be presented, together with preliminary evaluation of
compounds morphological behaviour in aqueous solution
New DC-SIGN ligands with a rigid core of controlled length
No full textHuman immunodeficiency virus (HIV) is still a huge health problem, causing the death of over 1 million people per year. The search for HIV-entry inhibitors represents a promising challenge to prevent HIV infection. In this field, DC-SIGN, a receptor expressed at the surface of the mucosal dendritic cells and involved in the early stages of HIV infection, is an important cellular target.1 DC-SIGN is a calcium-dependant tetrameric lectin, which recognizes and binds high-mannose oligosaccharides displayed at the surface of HIV virus
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
DC-SIGN as a Target for Drug Development Based on Carbohydrates
No full textDC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a type II C-type lectin that functions as an adhesion molecule located on dendritic cells (DCs). It enables some of the functions of DCs, including migration, pathogen recognition, internalisation and processing, and their binding to T cells. HIV-1 has been reported to enter DCs by being bound to DC-SIGN, escaping the normal lytic pathway in DCs' endosomes and avoiding the immune system defence system. A very similar mechanism of survival has been observed for some other pathogens. This makes DC-SIGN a receptor of interest in the design of distinctive anti-infectives that would inhibit DC-SIGN-pathogen interaction by blocking the very first step in pathogen infection. In this review we outline the development of DC-SIGN antagonists, focusing mainly on a glycomimetic approach. Based on the fact that DC-SIGN binds mannose- and fucose-based oligo- and polysaccharides, their structural mimics have been designed and proved to inhibit pathogen-DC-SIGN interaction. Furthermore, recent in vitro studies have demonstrated that DC-SIGN antagonists block effectively the transmission of pathogens like HIV-1 and Ebola to CD4+ T cells. Although DC-SIGN has not been validated in vivo as a druggable target yet, we await future DC-SIGN antagonists as a new and highly promising group of novel anti-infectives
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