Inhibition of arenavirus multiplication in vitro by phenotiazines
Inhibition of arenavirus multiplication in vitro by phenotiazines
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DOI：
10.1016/0166-3542(96)06956-2
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发表时间：
1996-07-01
影响因子：
7.6
通讯作者：
Damonte, EB
中科院分区：
文献类型：
--
作者：
Candurra, NA;Maskin, L;Damonte, EB
研究了三氟拉嗪（TFP）和氯丙嗪（CPZ）两种具有药理活性的吩噻嗪衍生物对阿根廷出血热病原沙粒病毒Junin （JV）、Tacaribe病毒和Pichinde病毒复制的抑制作用。这两种化合物在不影响细胞活力的浓度下对病毒增殖具有浓度依赖的抑制作用。CPZ对包括1株人病原株在内的多株JV的50%抑制浓度（IC50）在7.7 ~ 23.0 μ M之间，90%抑制浓度（IC90）在16.6 ~ 35.2 μ M之间波动。通过加除实验，CPZ抑制了JV复制周期的早期阶段，可能是病毒进入的阶段。在病毒吸附后不久加入TFP也会影响JV渗透；在感染7小时后加入TFP也会干扰病毒成熟的后期步骤。免疫荧光染色显示，在化合物存在的情况下，感染细胞细胞质中病毒抗原的表达高度降低，而细胞膜上未检测到JV蛋白。用吩噻嗪处理后，病毒蛋白的分布模式在少数显示阳性荧光的细胞中发生改变。在5 μ M钙调素的作用下，tfp对JV增殖的抑制作用被显著逆转。这些数据表明，TFP和CPZ抑制JV的体外复制。我们的研究结果表明，肌动蛋白微丝的完整性可能是最佳沙粒病毒增殖所必需的。
Trifluoperazine (TFP) and chlorpromazine (CPZ), two pharmacologically active phenotiazine derivatives, were evaluated for their inhibitory activity on the replication of the arenaviruses Junin (JV), the etiological agent of Argentine hemorrhagic fever, Tacaribe virus and Pichinde virus. Both compounds achieved a concentration-dependent inhibition of viral multiplication at concentrations not affecting cell viability. The 50% inhibitory concentration (IC50) values determined by a virus yield inhibition assay for several strains of JV, including a human pathogenic strain, were in the range of 7.7-23.0 mu M and the 90% inhibitory concentration (IC90) fluctuated between 16.6 and 35.2 mu M. From rime of addition and removal experiments, it can be concluded that CPZ inhibited an early stage in the replicative cycle of JV, probably viral entry. TFP also affected JV penetration when present soon after virus adsorption: and also interfered with a later step of viral maturation when added after 7 h of infection. The expression of viral antigens in the cytoplasm of infected cells was highly reduced in the presence of the compounds, as revealed by immunofluorescence staining, whereas no JV proteins were detected at the cell membrane. The distribution pattern of viral proteins was altered in the few cells exhibiting positive fluorescence after treatment with the phenotiazines. The TFP-induced inhibitory effect on JV multiplication was significantly reversed in the presence of 5 mu M calmodulin. These data indicate that TFP and CPZ inhibit JV replication in vitro. Our findings suggest that the integrity of the actin microfilaments may be required for optimal arenavirus multiplication.