Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity.
Structure-Based Design and Development of Chemical Probes Targeting Putative MOR-CCR5 Heterodimers to Inhibit Opioid Exacerbated HIV-1 Infectivity.
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DOI：
10.1021/acs.jmedchem.1c00408
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发表时间：
2021-06-10
影响因子：
7.3
通讯作者：
Zhang, Yan
中科院分区：
文献类型：
--
作者：
Huang, Boshi;Wang, Huiqun;Zheng, Yi;Li, Mengchu;Kang, Guifeng;Barreto-de-Souza, Victor;Nassehi, Nima;Knapp, Pamela E.;Selley, Dana E.;Hauser, Kurt F.;Zhang, Yan
配体结合的G蛋白偶联受体的晶体结构为合理设计分子探针提供了有形的模板。在此，我们报告了基于结构的设计，化学合成和生物学研究的双价配体靶向假定μ阿片受体C ─ C基序趋化因子配体5（MOR-CCR 5）异二聚体。与之前报道的二价配体相比，二价配体VZMC 013对莫尔和CCR 5都具有纳摩尔水平的结合亲和力，抑制CCL 5刺激的钙动员，并显着提高抗HIV-1 BaL活性。VZMC 013在共表达CCR 5和莫尔的TZM-bl细胞中抑制病毒感染的程度大于单独表达CCR 5的细胞。此外，VZMC013以浓度依赖性方式阻断人类免疫缺陷病毒（HIV）-1进入外周血单核细胞（PBMC）细胞，并在植物血凝素刺激的PBMC细胞中比在不存在阿片类药物的情况下更有效地抑制阿片类药物加速的HIV-1进入。构建了VZMC013与MOR-CCR 5异二聚体复合物结合的三维分子模型，以阐明其作用机制。VZMC013是靶向MOR-CCR 5异二聚体的有效化学探针，可作为抑制阿片类药物加剧的HIV-1进入的药理学试剂。
Crystal structures of ligand-bound G-protein-coupled receptors provide tangible templates for rationally designing molecular probes. Herein, we report the structure-based design, chemical synthesis, and biological investigations of bivalent ligands targeting putative mu opioid receptor C─C motif chemokine ligand 5 (MOR-CCR5) heterodimers. The bivalent ligand VZMC013 possessed nanomolar level binding affinities for both the MOR and CCR5, inhibited CCL5-stimulated calcium mobilization, and remarkably improved anti-HIV-1BaL activity over previously reported bivalent ligands. VZMC013 inhibited viral infection in TZM-bl cells coexpressing CCR5 and MOR to a greater degree than cells expressing CCR5 alone. Furthermore, VZMC013 blocked human immunodeficiency virus (HIV)-1 entry in peripheral blood mononuclear cells (PBMC) cells in a concentration-dependent manner and inhibited opioid-accelerated HIV-1 entry more effectively in phytohemagglutinin-stimulated PBMC cells than in the absence of opioids. A three-dimensional molecular model of VZMC013 binding to the MOR-CCR5 heterodimer complex is constructed to elucidate its mechanism of action. VZMC013 is a potent chemical probe targeting MOR-CCR5 heterodimers and may serve as a pharmacological agent to inhibit opioid-exacerbated HIV-1 entry.
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DOI：
10.1097/qad.0b013e3283639804
发表时间：
2013-09-10
期刊：
AIDS (London, England)
影响因子：
--
作者：
El-Hage N;Dever SM;Podhaizer EM;Arnatt CK;Zhang Y;Hauser KF
通讯作者：
Hauser KF
影响因子：
5
作者：
Chen, CG;Li, J;Liu-Chen, LY
通讯作者：
Liu-Chen, LY
影响因子：
4.8
作者：
Garcia-Perez, Javier;Rueda, Patricia;Kellenberger, Esther
通讯作者：
Kellenberger, Esther
影响因子：
2.8
作者：
Danner, P;Bauer, M;Maier, ME
通讯作者：
Maier, ME
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P