1,720,972 research outputs found
PSEUDO-GLYCODENDRIMERS CONTAINING A MOLECULAR ROD CORE: SYNTHESIS, CHARACTERIZATION AND DC-SIGN ANTAGONISM
Full text linkHuman 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 carbohydrate-recognizing receptor expressed at the surface of the mucosal dendritic cells and involved in the early stages of HIV infection, is an important cellular target. The use of artificial molecules presenting 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 pseudo-glycodendrimers characterized by rigid molecular rods that rationally space active ligands, with the aim to exploit both the statistical rebinding and the chelating binding modes. Compounds were synthesised by varying the length of the rigid rod, the nature as well as the valency of the sugar moieties and the linkers flexibility. The optimal combination of active monovalent ligand, scaffold and valency led to a nanomolar inhibitor of DC-SIGN-mediated adhesion of HIV on cells. Compounds' biological performances were evaluated through Surface Plasmon Resonance Inhibition assays and trans-infection inhibition assays; the interaction between artificial compounds and DC-SIGN expressing cells was evaluated through confocal micoscopy, given the intrinsic fluorescence of the rods. Morphological behaviour of glycodendrimers was investigated using several analytical techniques, demonstrating that they are mainly monomers in solution, despite their amphiphilic structure. Finally, modifications of monovalent ligands were performed in order to improve compounds selectivity vs Langerin
Multivalent DC-SIGN ligands with a rigid core of controlled lenght
No full textHuman immunodeficiency virus (HIV) is still a huge health problem of the 21st century, 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, dendritic cell-specific ICAM-3 grabbing non-integrine (DC-SIGN), expressed at the surface of the mucosal dendritic cells (DC) and involved in the early stages of HIV infection, is an important cellular target.1
DC-SIGN is a calcium-dependant tetrameric lectin; it recognizes high-mannose oligosaccharides displayed at the surface of HIV virus and interacts with them through strong multiple interactions. Therefore, artificial molecules displaying multivalent carbohydrate moieties, able to interact with DC-SIGN with good affinity, should prevent HIV attachment to DC and therefore HIV infection.
In our group, several DC-SIGN mannose-based ligands have been prepared and tested as HIV inhibitors; glycomimetic compounds were used rather than native oligosaccharides.2, 3
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.
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 tests results will be presented
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
Novel cyclometallated pincer of pt(ii) alkyne complexes with interesting luminescent properties
No full textOrganometallic complexes of transition-metals have recently received considerable attention as phosphorescent emitters for Organic Light Emitting Diodes (OLEDs), owing to their remarkable luminescent properties [1]. In particular, halide complexes of platinum (II) based on cyclometallated 1,3-di(2-pyridyl)benzene ligand seem very promising in this respect because they are highly emissive [2]. Besides, it is well known that the substitution of weak-field halide ligands by strong-field acetylide, R–CC–, provides an example of how an increase in the ligand field strength of the ancillary ligand can promote luminescence [3].
These observations prompted us to prepare new cyclometallated Pt(II) complexes with a substituted 1,3-di(2-pyridil)benzene ligand (see figure) to get a better understanding of the effect on the emission and quantum yields of different R substituents and various acetylide ancillary ligands. It turned out that the prepared complexes are highly luminescent and can be used for the preparation of light-emitting devices. Details on this study will be presented.
R = Me, Mesityl Y = 3,5-difluorobenzene; dimethyl-phenyl-amine, pentafluorobenzene
[1] Evans, R.C.; Douglas, P.; Winscom, C.J. Coord. Chem. Rev. 2006, 250, 2093.
[2] Murphy, L.; Williams, J.A.G. in Topics in Organometallic Chemistry 28. Molecular Organometallic Materials for Optics, Le Bozec, H. and Guerchais V. (eds.), Springer Verlag Berlin Heidelberg 2010, pp 75-111.
[3] Williams, J. A. G.; Develay, S.; Rochester, D. L.; Murphy, L. Coord. Chem. Rev., 2008, 252, 2596; Lu,W.; Mi, B.-X.; Chan, M. C. W.; Hui, Z.; Che, C.-M.; Zhu, N.; Lee, S.-T. J. Am. Chem. Soc., 2004, 126, 4958
Novel cyclometalated Pt(II) complexes with interesting luminescent properties
No full textOrganometallic complexes of transition-metals have recently received considerable attention as phosphorescent emitters for Organic Light Emitting Diodes (OLEDs), owing to their remarkable luminescent properties1. In particular, various platinum(II) complexes with a cyclometallated 1,3-di(2-pyridyl)benzene ligand seem very promising in this respect because they are highly emissive.2
This observation prompted us to prepare new cyclometallated Pt(II) complexes with a substituted 1,3-di(2-pyridil)benzene ligand (see figure) to get a better understanding of the effect on the emission and quantum yields of different R substituents and various Y ancillary ligands.
It turned out that all the prepared complexes are highly luminescent and can be used for the preparation of light-emitting devices. Details on this study will be presented.
R = Me, Mesityl Y = Cl, variously substituited alkyne
References
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[1] R.C. Evans, P. Douglas, C.J.Winscom, Coord. Chem. Rev., 250, (2006), 2093-2126.
[2] L. Murphy, J.A.G.Williams, in Topics in Organometallic Chemistry 28. Molecular Organometallic Materials for Optics, Le Bozec, H. and Guerchais V. (eds.), Springer Verlag Berlin Heidelberg 2010, pp 75-111
A pseudo-glycodendrimer inhibits DC-sign-mediated HIV trans-infection and interferes with DC-sign signal
No full textBackground: DC-SIGN is involved in the initial stages of mucosal HIV infection. DC-SIGN, by binding mannosylated residues (high mannose glycan) on HIV gp120, mediates trans-infection of CD4 T cells. Furthermore HIV interaction with DC-SIGN subverts its normal immune-activating functions shifting the Th1/Th2 balance towards a Th2 response that favours the persistence of the virus. HIV binding to DC-SIGN induces intracellular signalling pathways that trigger activities required to viral replication and promote immunosuppressive responses by interfering with TLR signalling. Pseudo-mannosylated compounds were synthesized in the attempt to compete with the binding of DC-SIGN to HIV gp120 and interfere with the immunosuppressive DC-SIGN signalling.
Methods: A hexavalent pseudo-glycodendrimer (PM26) able to interact selectively with DC-SIGN was synthesized. The ability of PM26 to inhibit HIV-1 trans-infection was assessed in cellular models based on DC-SIGN expressing B-THP-1 cells. To study the effects of PM26 on DC-SIGN signal, gene expression profile after treatment of human monocyte-derived DCs with PM26 in presence/absence of TLR agonist (LPS and Poly:IC) was evaluated. The cytotoxicity of the compound was also assessed.
Results: PM26 abrogated almost completely (>98%) the transmission of different HIV strains (Bal, Du174) to CD4 T cells at 1 μM, with an IC50 of 25 nM.
Treatment of DCs with PM26 in presence/absence of LPS or Poly:IC strongly increased the expression of cytokines that regulate innate immunity, such as IL-1β, IL-6, TNFα and IL-12. Interestingly, an upregulation of IRF8, involved in the regulation of IL-12 expression, was observed. PM26 also induced IFNγ and CCL3, CCL4 and CCL7.
TAPBP, involved in antigen presentation, and TLR9, were up regulated as well. In contrast, the compound did not augment IL-10, CCR5, CXCR4 and DC-SIGN expression. No toxicity was observed at the concentrations tested in the cellular assays.
Conclusion: The pseudo-glycodendrimer PM26 inhibits HIV-1 trans-infection by competing with the binding of the virus to DC-SIGN. Furthermore, PM26 both alone and in synergy with TLR agonist stimulates early immune responses that contribute to counteract HIV infection and activate adaptive immunity. These features make the compound a potential candidate for the development as topical microbicide
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