Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4
Inhibition of HIV Fusion by Small Molecule Agonists through Efficacy-Engineering of CXCR4
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DOI：
10.1021/acschembio.8b00061
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发表时间：
2018-04-01
影响因子：
4
通讯作者：
Rosenkilde, Mette Marie
中科院分区：
文献类型：
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作者：
Berg, Christian;Daugvilaite, Viktorija;Rosenkilde, Mette Marie
CXC 趋化因子受体 4 (CXCR4) 参与多种生理和病理过程，特别是作为人类免疫缺陷病毒 (HIV) 细胞进入的辅助受体。其广泛的表达模式和至关重要的生物学重要性使 CXCR4 成为一个麻烦的药物靶点，因为破坏其与内源性配体 CXC 趋化因子配体 12 (CXCL12) 的相互作用会产生严重后果。事实上，只有一种 CXCR4 药物，bicyclam 拮抗剂和 HIV 进入抑制剂 AMD3100（Plerixafor/Mozobil）已被批准用于临床，但仅用于 CXCR4 拮抗作用导致的干细胞动员。在这里，我们报告了跨膜螺旋 7 中部 CXCR4-F292A(7.43) 的功效转换突变工程，该突变将拮抗剂 AMD3100 和 AMD11070 转化为部分激动剂。作为 F292A CXCR4 的激动剂，AMD3100 和 AMD11070 对 CXCR4 信号传导的干扰较小，同时它们仍然是 HIV 融合的有效抑制剂。这表明小分子 CXCR4 激动剂可以具有作为 HIV 进入抑制剂的治疗潜力。
CXC chemokine receptor 4 (CXCR4) is involved in multiple physiological and pathological processes, notably as a coreceptor for human immunodeficiency virus (HIV) cell entry. Its broad expression pattern and vital biological importance make CXCR4 a troublesome drug target, as disruption of the interaction with its endogenous ligand, CXC chemokine ligand 12 (CXCL12), has severe consequences. In fact, only one CXCR4 drug, the bicyclam antagonist and HIV entry inhibitor AMD3100 (Plerixafor/Mozobil), has been approved for clinical use, however only for stem cell mobilization a consequence of CXCR4 antagonism. Here, we report the engineering of an efficacy switch mutation in CXCR4-F292A(7.43) in the middle of transmembrane helix 7 that converted the antagonists AMD3100 and AMD11070 into partial agonists. As agonists on F292A CXCR4, AMD3100 and AMD11070 were less disruptive to CXCR4 signaling while they remained efficient inhibitors of HIV fusion. This demonstrates that small molecule CXCR4 agonists can have a therapeutic potential as HIV entry inhibitors.