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  1. Article ; Online: Exploration of Pyrido[3,4- d ]pyrimidines as Antagonists of the Human Chemokine Receptor CXCR2

    Max Van Hoof / Sandra Claes / Katrijn Boon / Tom Van Loy / Dominique Schols / Wim Dehaen / Steven De Jonghe

    Molecules, Vol 28, Iss 2099, p

    2023  Volume 2099

    Abstract: Upregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, ...

    Abstract Upregulated CXCR2 signalling is found in numerous inflammatory, autoimmune and neurodegenerative diseases, as well as in cancer. Consequently, CXCR2 antagonism is a promising therapeutic strategy for treatment of these disorders. We previously identified, via scaffold hopping, a pyrido[3,4- d ]pyrimidine analogue as a promising CXCR2 antagonist with an IC 50 value of 0.11 µM in a kinetic fluorescence-based calcium mobilization assay. This study aims at exploring the structure–activity relationship (SAR) and improving the CXCR2 antagonistic potency of this pyrido[3,4- d ]pyrimidine via systematic structural modifications of the substitution pattern. Almost all new analogues completely lacked the CXCR2 antagonism, the exception being a 6-furanyl-pyrido[3,4- d ]pyrimidine analogue (compound 17b ) that is endowed with similar antagonistic potency as the original hit.
    Keywords CXCR2 antagonists ; pyrido[3,4- d ]pyrimidines ; SAR study ; Organic chemistry ; QD241-441
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: CXCR7/ACKR3-targeting ligands interfere with X7 HIV-1 and HIV-2 entry and replication in human host cells

    Thomas D'huys / Sandra Claes / Tom Van Loy / Dominique Schols

    Heliyon, Vol 4, Iss 3, Pp e00557- (2018)

    2018  

    Abstract: Chemokine receptors CCR5 and CXCR4 are considered the main coreceptors for initial HIV infection, replication and transmission, and subsequent AIDS progression. Over the years, other chemokine receptors, belonging to the family of G protein-coupled ... ...

    Abstract Chemokine receptors CCR5 and CXCR4 are considered the main coreceptors for initial HIV infection, replication and transmission, and subsequent AIDS progression. Over the years, other chemokine receptors, belonging to the family of G protein-coupled receptors, have also been identified as candidate coreceptors for HIV entry into human host cells. Amongst them, CXCR7, also known as atypical chemokine receptor 3 (ACKR3), was suggested as a coreceptor candidate capable of facilitating both HIV-1 and HIV-2 entry in vitro. In this study, a cellular infection model was established to further decipher the role of CXCR7 as an HIV coreceptor. Using this model, CXCR7-mediated viral entry was demonstrated for several clinical HIV isolates as well as laboratory strains. Of interest, the X4-tropic HIV-1 HE strain showed rapid adaptation towards CXCR7-mediated infection after continuous passaging on CD4- and CXCR7-expressing cells. Furthermore, we uncovered anti-CXCR7 monoclonal antibodies, small molecule CXCR7 inhibitors and the natural CXCR7 chemokine ligands as potent inhibitors of CXCR7 receptor-mediated HIV entry and replication. Even though the clinical relevance of CXCR7-mediated HIV infection remains poorly understood, our data suggest that divergent HIV-1 and HIV-2 strains can quickly adapt their coreceptor usage depending on the cellular environment, which warrants further investigation.
    Keywords Infectious disease ; Virology ; Cell biology ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
    Subject code 570
    Language English
    Publishing date 2018-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Synthesis and Anti-HIV Activity of a Novel Series of Isoquinoline-Based CXCR4 Antagonists

    Mastaneh Safarnejad Shad / Sandra Claes / Eline Goffin / Tom Van Loy / Dominique Schols / Steven De Jonghe / Wim Dehaen

    Molecules, Vol 26, Iss 6297, p

    2021  Volume 6297

    Abstract: An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 ... ...

    Abstract An expansion of the structure–activity relationship study of CXCR4 antagonists led to the synthesis of a series of isoquinolines, bearing a tetrahydroquinoline or a 3-methylpyridinyl moiety as head group. All compounds were investigated for CXCR4 affinity and antagonism in competition binding and calcium mobilization assays, respectively. In addition, the anti-HIV activity of all analogues was determined. All compounds showed excellent activity, with compound 24c being the most promising one, since it displayed consistently low nanomolar activity in the various assays.
    Keywords isoquinoline ; CXCR4 antagonist ; HIV ; Organic chemistry ; QD241-441
    Language English
    Publishing date 2021-10-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Comparison of cell-based assays for the identification and evaluation of competitive CXCR4 inhibitors.

    Anneleen Van Hout / Thomas D'huys / Merel Oeyen / Dominique Schols / Tom Van Loy

    PLoS ONE, Vol 12, Iss 4, p e

    2017  Volume 0176057

    Abstract: The chemokine receptor CXCR4 is activated by its unique chemokine ligand CXCL12 and regulates many physiological and developmental processes such as hematopoietic cell trafficking. CXCR4 is also one of the main co-receptors for human immunodeficiency ... ...

    Abstract The chemokine receptor CXCR4 is activated by its unique chemokine ligand CXCL12 and regulates many physiological and developmental processes such as hematopoietic cell trafficking. CXCR4 is also one of the main co-receptors for human immunodeficiency virus (HIV) entry. Dysfunction of the CXCL12/CXCR4 axis contributes to several human pathologies, including cancer and inflammatory diseases. Consequently, inhibition of CXCR4 activation is recognized as an attractive target for therapeutic intervention. In this regard, numerous agents modifying CXCR4 activity have been evaluated in in vitro experimental studies and pre-clinical models. Here, we evaluated a CXCL12 competition binding assay for its potential as a valuable initial screen for functional and competitive CXCR4 inhibitors. In total, 11 structurally diverse compounds were included in a side-by-side comparison of in vitro CXCR4 cell-based assays, such as CXCL12 competition binding, CXCL12-induced calcium signaling, CXCR4 internalization, CXCL12-guided cell migration and CXCR4-specific HIV-1 replication experiments. Our data indicated that agents that inhibit CXCL12 binding, i.e. the anti-CXCR4 peptide analogs T22, T140 and TC14012 and the small molecule antagonists AMD3100, AMD3465, AMD11070 and IT1t showed inhibitory activity with consistent relative potencies in all further applied CXCR4-related assays. Accordingly, agents exerting no or very weak receptor binding (i.e., CTCE-9908, WZ811, Me6TREN and gambogic acid) showed no or very poor anti-CXCR4 inhibitory activity. Thus, CXCL12 competition binding studies were proven to be highly valuable as an initial screening assay and indicative for the pharmacological and functional profile of competitive CXCR4 antagonists, which will help the design of new potent CXCR4 inhibitors.
    Keywords Medicine ; R ; Science ; Q
    Subject code 570
    Language English
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Quasispecies analysis of JC virus DNA present in urine of healthy subjects.

    Tom Van Loy / Kim Thys / Luc Tritsmans / Lieven J Stuyver

    PLoS ONE, Vol 8, Iss 8, p e

    2013  Volume 70950

    Abstract: JC virus is a human polyomavirus that infects the majority of people without apparent symptoms in healthy subjects and it is the causative agent of progressive multifocal leucoencephalopathy (PML), a disorder following lytic infection of oligodendrocytes ...

    Abstract JC virus is a human polyomavirus that infects the majority of people without apparent symptoms in healthy subjects and it is the causative agent of progressive multifocal leucoencephalopathy (PML), a disorder following lytic infection of oligodendrocytes that mainly manifests itself under immunosuppressive conditions. A hallmark for JC virus isolated from PML-brain is the presence of rearrangements in the non-coding control region (NCCR) interspersed between the early and late genes on the viral genome. Such rearrangements are believed to originate from the archetype JC virus which is shed in urine by healthy subjects and PML patients. We applied next generation sequencing to explore the non-coding control region variability in urine of healthy subjects in search for JC virus quasispecies and rearrangements reminiscent of PML. For 61 viral shedders (out of a total of 254 healthy subjects) non-coding control region DNA and VP1 (major capsid protein) coding sequences were initially obtained by Sanger sequencing. Deletions between 1 and 28 nucleotides long appeared in ∼24.5% of the NCCR sequences while insertions were only detected in ∼3.3% of the samples. 454 pyrosequencing was applied on a subset of 54 urine samples demonstrating the existence of JC virus quasispecies in four subjects (∼7.4%). Hence, our results indicate that JC virus DNA in urine is not always restricted to one unique virus variant, but can be a mixture of naturally occurring variants (quasispecies) reflecting the susceptibility of the non-coding control region for genomic rearrangements in healthy individuals. Our findings pave the way to explore the presence of viral quasispecies and the altered viral tropism that might go along with it as a potential risk factor for opportunistic secondary infections such as PML.
    Keywords Medicine ; R ; Science ; Q
    Subject code 616
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Signaling properties of the human chemokine receptors CXCR4 and CXCR7 by cellular electric impedance measurements.

    Jordi Doijen / Tom Van Loy / Wouter De Haes / Bart Landuyt / Walter Luyten / Liliane Schoofs / Dominique Schols

    PLoS ONE, Vol 12, Iss 9, p e

    2017  Volume 0185354

    Abstract: The chemokine receptor 4 (CXCR4) and 7 (CXCR7) are G-protein-coupled receptors involved in various diseases including human cancer. As such, they have become important targets for therapeutic intervention. Cell-based receptor assays, able to detect ... ...

    Abstract The chemokine receptor 4 (CXCR4) and 7 (CXCR7) are G-protein-coupled receptors involved in various diseases including human cancer. As such, they have become important targets for therapeutic intervention. Cell-based receptor assays, able to detect agents that modulate receptor activity, are of key importance for drug discovery. We evaluated the potential of cellular electric impedance for this purpose. Dose-dependent and specific stimulation of CXCR4 was detected upon addition of its unique chemokine ligand CXCL12. The response magnitude correlated with the CXCR4 expression level. Gαi coupling and signaling contributed extensively to the impedance response, whereas Gαq- and Gβγ-related events had only minor effects on the impedance profile. CXCR7 signaling could not be detected using impedance measurements. However, increasing levels of CXCR7 expression significantly reduced the CXCR4-mediated impedance readout, suggesting a regulatory role for CXCR7 on CXCR4-mediated signaling. Taken together, cellular electric impedance spectroscopy can represent a valuable alternative pharmacological cell-based assay for the identification of molecules targeting CXCR4, but not for CXCR7 in the absence of CXCR4.
    Keywords Medicine ; R ; Science ; Q
    Subject code 500
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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