靶向假定的μ阿片受体和趋化因子受体CXCR4二聚体的双价配体在阿片类药物增强HIV-1进入过程中的作用
Bivalent Ligand Aiming Putative Mu Opioid Receptor and Chemokine Receptor CXCR4 Dimers in Opioid Enhanced HIV-1 Entry.
作者信息
Ma Hongguang, Wang Huiqun, Li Mengchu, Barreto-de-Souza Victor, Reinecke Bethany A, Gunta Rama, Zheng Yi, Kang Guifeng, Nassehi Nima, Zhang Huijun, An Jing, Selley Dana E, Hauser Kurt F, Zhang Yan
机构信息
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E Leigh Street, Richmond, Virginia 23298, United States.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States.
出版信息
ACS Med Chem Lett. 2020 Sep 13;11(11):2318-2324. doi: 10.1021/acsmedchemlett.0c00444. eCollection 2020 Nov 12.
A bivalent compound featuring both a mu opioid receptor (MOR) and a CXCR4 antagonist pharmacophore (naltrexone and IT1t) was designed and synthesized. Further binding and functional studies demonstrated acting as a MOR and a CXCR4 dual antagonist with reasonable binding affinities at both receptors. Furthermore, compound seemed more effective than a combination of IT1t and naltrexone in inhibiting HIV entry at the presence of morphine. Additional molecular modeling results suggested that may bind with the putative MOR-CXCR4 heterodimer to induce its anti-HIV activity. Collectively, bivalent ligand may serve as a promising lead to develop chemical probes targeting the putative MOR-CXCR4 heterodimer in comprehending opioid exacerbated HIV-1 invasion.
设计并合成了一种同时具有μ阿片受体（MOR）和CXCR4拮抗剂药效基团（纳曲酮和IT1t）的二价化合物。进一步的结合和功能研究表明，该化合物作为MOR和CXCR4双重拮抗剂，对两种受体均具有合理的结合亲和力。此外，在吗啡存在的情况下，该化合物在抑制HIV进入方面似乎比IT1t和纳曲酮的组合更有效。额外的分子模拟结果表明，该化合物可能与假定的MOR-CXCR4异二聚体结合以诱导其抗HIV活性。总的来说，二价配体可能是开发针对假定的MOR-CXCR4异二聚体的化学探针的有前景的先导物，有助于理解阿片类药物加剧的HIV-1入侵。
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