Filovirus Antiviral Activity of Cationic Amphiphilic Drugs is Associated with Lipophilicity and Ability To Induce Phospholipidosis
Filovirus Antiviral Activity of Cationic Amphiphilic Drugs is Associated with Lipophilicity and Ability To Induce Phospholipidosis
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DOI：
10.1128/aac.00143-20
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发表时间：
2020-08-01
影响因子：
4.9
通讯作者：
von Hahn, Thomas
中科院分区：
文献类型：
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作者：
Gunesch, Antonia P.;Zapatero-Belinchon, Francisco J.;von Hahn, Thomas
已经发现几种阳离子两亲性药物（CADS）抑制丝状病毒和其他包膜病毒的细胞进入。结构无关的CAD可能具有抗病毒活性，但其潜在的共同机制和结构-活性关系尚未完全了解。我们的目的是了解如何广泛的抗病毒活性之间的CAD和结构和物理化学性质与进入抑制。我们测量了45种异质性和大多数FDA批准的CAD对马尔堡病毒假颗粒（MARVpp）细胞进入的抑制作用以及EA.hy926细胞中的细胞毒性。我们分析了抗病毒活性与四个化学性质的相关性：pKa，疏水性（辛醇/水分配系数; ClogP），分子量，以及碱性基团和疏水环结构之间的距离。此外，我们通过流式细胞术定量了CAD亚组的药物诱导磷脂质病（DIPL）。通过两种计算机相似性搜索方法获得结构相似的化合物（衍生物）和具有相似化学性质但与强抑制剂结构无关的化合物（类似物），并测试其抗病毒活性。总体而言，45种CAD中有11种（24%）抑制MARVpp 40%或更多。最强的抗病毒化合物是决奈达隆、三羟甲基纤维素和奎纳克林。结构-活性关系研究揭示了抗病毒活性、疏水性（ClogP > 4）和DIPL之间的高度显著相关性。此外，pKa和疏水和亲水部分之间的分子内距离与抗病毒活性，但在较小程度上。我们还表明，与类似物相反，衍生物具有与种子化合物决奈达隆相似的抗病毒活性。总体而言，四分之一的CAD在体外抑制MARVpp进入，CAD的抗病毒活性主要依赖于其疏水性，但由个体结构促进。
Several cationic amphiphilic drugs (CADS) have been found to inhibit cell entry of filoviruses and other enveloped viruses. Structurally unrelated CADs may have antiviral activity, yet the underlying common mechanism and structure-activity relationship are incompletely understood. We aimed to understand how widespread antiviral activity is among CADs and which structural and physicochemical properties are linked to entry inhibition. We measured inhibition of Marburg virus pseudoparticle (MARVpp) cell entry by 45 heterogeneous and mostly FDA-approved CADs and cytotoxicity in EA.hy926 cells. We analyzed correlation of antiviral activity with four chemical properties: pKa, hydrophobicity (octanol/water partitioning coefficient; ClogP), molecular weight, and distance between the basic group and hydrophobic ring structures. Additionally, we quantified drug-induced phospholipidosis (DIPL) of a CAD subset by flow cytometry. Structurally similar compounds (derivatives) and those with similar chemical properties but unrelated structures (analogues) to those of strong inhibitors were obtained by two in silico similarity search approaches and tested for antiviral activity. Overall, 11 out of 45 (24%) CADs inhibited MARVpp by 40% or more. The strongest antiviral compounds were dronedarone, triparanol, and quinacrine. Structure-activity relationship studies revealed highly significant correlations between antiviral activity, hydrophobicity (ClogP > 4), and DIPL. Moreover, pKa and intramolecular distance between hydrophobic and hydrophilic moieties correlated with antiviral activity but to a lesser extent. We also showed that in contrast to analogues, derivatives had antiviral activity similar to that of the seed compound dronedarone. Overall, one-quarter of CADs inhibit MARVpp entry in vitro, and antiviral activity of CADs mostly relies on their hydrophobicity yet is promoted by the individual structure.