作者: Belmont, Philippe ; Sari, Marie-Agnès ; Helissey, Philippe ; Merlet, Eric ; Giorgi-Renault, Sylviane ; Aknin, Karen ; Desbène-Finck, Stéphanie ; Bontemps, Alexis ; Farce, Amaury ; Chavatte, Philippe

New polycyclic heterocycles were synthesised and evaluated as potential inhibitors of thymidine phosphorylase (TP). Inspired by the pharmacophoric pyrimidinedione core of the natural substrate, four series have been designed in order to interact with large empty pockets of the active site: pyrimidoquinoline-2,4-diones (series A), pyrimidinedione linked to a pyrroloquinoline-1,3-diones (series B and C), the polycyclic heterocycle has been replaced by a pyrimidopyridopyrrolidinetetraone (series D). In each series, the tricyclic nitrogen heterocyclic moiety has been synthesised by a one-pot multicomponent reaction. Compared to 7-DX used as control, 2d, 2l, 2p (series A), 28a (series D), and the open intermediate 30 showed modest to good activities. A kinetic study confirmed that the most active compounds 2d, 2p are competitive inhibitors. Molecular docking analysis confirmed the interaction of these new compounds at the active binding site of TP and highlighted a plausible specific interaction in a pocket that had not yet been explored.

2022-10-01·European Journal of Pharmacology

7-Methoxyisoflavone suppresses vascular endothelial inflammation by inhibiting the expression of endothelial adhesion molecules

Article

作者: Guo, Yi ; Zhu, Jingbo ; Liu, Kaiyuan ; Zhu, Xinyu ; Yang, Liuye ; Wang, Pengchao ; Liang, Minglu ; Deng, Shan ; Peng, Jiangtong

Endothelial cells (ECs) are vital regulators of inflammatory processes, there is the potential for inhibition of EC inflammation to be a therapeutic target in chronic inflammatory diseases. This study aimed to investigate the effect of 7-methoxyisoflavone (7-Mif) on endothelial inflammation. Our results showed that 7-Mif have no cytotoxicity on HUVECs. Pretreatment with 5 μM, 10 μM and 50 μM 7-Mif significantly reduced IL-1β-induced ICAM-1 (28.1% ± 4.1%, 25.9 ± 2.5% and 32.0% ± 3.2%, respectively) and VCAM-1 (48.0% ± 5.6%, 40.1 ± 3.1% and 39.6% ± 3.1%, respectively) mRNA expression. And pretreatment with 10 μM and 50 μM 7-Mif significantly reduced IL-1β-induced ICAM-1 (45.1% ± 4.4% and 33.6 ± 4.4%, respectively) and VCAM-1 (53.0% ± 3.7% and 53.7 ± 5.1%, respectively) protein levels. Furthermore, pretreatment with 50 μM 7-Mif inhibited monocyte-endothelial cell adhesion (50.2% ± 4.2%). Mechanistically, our results showed that 7-Mif reversed IL-1β-induced NF-κB activation and p65 translocation to the nucleus, therefore inhibiting endothelial cell inflammation. In addition, we confirmed that 7-Mif 10 mg/kg and 20 mg/kg reduced LPS-induced ICAM-1 (47.3% ± 1.3% and 39.0% ± 3.2%, respectively) and VCAM-1 (56.5 ± 2.8% and 47.8 ± 4.3%, respectively) expression and attenuated inflammatory injury in mice. In conclusion, we showed the inhibitory effect of 7-Mif on endothelial inflammation by suppressing the expression of endothelial adhesion molecules and monocyte adhesion. Our data illustrated that 7-Mif could positively regulate the process of endothelial inflammation.

2022-03-07·Journal of Experimental Medicine1区 · 医学

Epitope convergence of broadly HIV-1 neutralizing IgA and IgG antibody lineages in a viremic controller

1区 · 医学

Article

作者: Plevka, Pavel ; Schwartz, Olivier ; Dimitrov, Jordan D. ; Fernández, Ignacio ; Fiquet, Oriane ; Guivel-Benhassine, Florence ; Girelli-Zubani, Giulia ; Scheid, Johannes F. ; Planchais, Cyril ; Seaman, Michael S. ; Péhau-Arnaudet, Gérard ; Bouvin-Pley, Mélanie ; Hrebík, Dominik ; Walker, Bruce D. ; Sanders, Rogier W. ; Masse-Ranson, Guillemette ; Bontems, François ; Mouquet, Hugo ; Di Santo, James P. ; Lorin, Valérie ; Molinos-Albert, Luis M. ; Hieu, Thierry ; Rey, Félix A. ; Braibant, Martine

Decrypting the B cell ontogeny of HIV-1 broadly neutralizing antibodies (bNAbs) is paramount for vaccine design. Here, we characterized IgA and IgG bNAbs of three distinct B cell lineages in a viremic controller, two of which comprised only IgG+ or IgA+ blood memory B cells; the third combined both IgG and IgA clonal variants. 7-269 bNAb in the IgA-only lineage displayed the highest neutralizing capacity despite limited somatic mutation, and delayed viral rebound in humanized mice. bNAbs in all three lineages targeted the N332 glycan supersite. The 2.8-Å resolution cryo-EM structure of 7-269-BG505 SOSIP.664 complex showed a similar pose as 2G12, on an epitope mainly composed of sugar residues comprising the N332 and N295 glycans. Binding and cryo-EM structural analyses showed that antibodies from the two other lineages interact mostly with glycans N332 and N386. Hence, multiple B cell lineages of IgG and IgA bNAbs focused on a unique HIV-1 site of vulnerability can codevelop in HIV-1 viremic controllers.

100 项与 7-series (Ruga) 相关的药物交易

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