Antiviral activity of lovastatin against respiratory syncytial virus in vivo and in vitro
Antiviral activity of lovastatin against respiratory syncytial virus in vivo and in vitro
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DOI：
10.1128/aac.45.4.1231-1237.2001
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发表时间：
2001-04-01
影响因子：
4.9
通讯作者：
Graham, BS
中科院分区：
文献类型：
--
作者：
Gower, TL;Graham, BS
呼吸道合胞病毒（RSV）是一种重要的人类病原体，可引起婴儿和免疫功能低下的成人严重和危及生命的呼吸道感染。我们最近发现介导病毒融合的RSV F糖蛋白与RhoA结合。RhoA活化的一个步骤涉及香叶基转移酶在蛋白质的羧基端进行异戊二烯化。这种修饰允许RhoA附着在质膜内小叶的磷脂酰丝氨酸上。洛伐他汀（lovastatin）是一种通过直接抑制羟甲基戊二酰辅酶a还原酶抑制细胞内戊烯酰化途径的药物，在RSV感染后24小时内给药可减少RSV，但不能减少牛痘病毒的复制，并减少病毒引起的小鼠体重减轻和疾病。复制的抑制不太可能是由于抑制胆固醇的生物合成，因为另一种降胆固醇剂吉非非齐（gemfibrozil）不影响病毒的复制，而且在实验的时间框架内洛伐他汀没有显著降低血清胆固醇水平。洛伐他汀还能减少细胞培养中的细胞间融合，并消除HEp-2细胞中的RSV复制。这些数据表明，洛伐他汀、更特异性的异戊二烯化抑制剂或其他预防RhoA膜定位的药药学方法，应被考虑作为一种预防性抗病毒治疗，用于严重RSV疾病高风险的特定患者群体，如住院老年人和骨髓或肺移植接受者。
Respiratory syncytial virus (RSV) is an important human pathogen that can cause severe and life-threatening respiratory infections in infants and immunocompromised adults. We have recently shown that the RSV F glycoprotein, which mediates viral fusion, binds to RhoA. One of the steps in RhoA activation involves isoprenylation at the carboxy terminus of the protein by geranylgeranyltransferase. This modification allows RhoA to be attached to phosphatidyl serine on the inner leaflet of the plasma membrane. Treatment of mice with lovastatin, a drug that inhibits prenylation pathways in the cell by directly inhibiting hydroxymethylglutaryl coenzyme A reductase, diminishes RSV but not vaccinia virus replication when administered up to 24 h after RSV infection and decreases virus-induced weight loss and illness in mice. The inhibition of replication is not likely due to the inhibition of cholesterol biosynthesis, since gemfibrozil, another cholesterol-lowering agent, did not affect virus replication and serum cholesterol levels were not significantly lowered by lovastatin within the time frame of the experiment. Lovastatin also reduces cell-to-cell fusion in cell culture and eliminates RSV replication in HEp-2 cells. These data indicate that lovastatin, more specific isoprenylation inhibitors, or other pharmacological approaches for preventing RhoA membrane localization should be considered for evaluation as a preventive antiviral therapy for selected groups of patients at high risk for severe RSV disease, such as the institutionalized elderly and bone marrow or lung transplant recipients.