Cao Wangsen, Baniecki Mary Lynn, McGrath William J, Bao Clare, Deming Clayton B, Rade Jeffrey J, Lowenstein Charles J, Mangel Walter F
Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
FASEB J. 2003 Dec;17(15):2345-6. doi: 10.1096/fj.03-0396fje. Epub 2003 Oct 2.
Nitric oxide (NO) is an antiviral effector of the innate immune system, but few of the viral targets of NO have been identified. We now show that NO inhibits adenovirus replication by targeting the adenovirus proteinase (AVP). NO generated from diethylamine NONOate (DEA-NONOate) or spermine NONOate (Sp-NONOate) inhibited the AVP. Inhibition was reversible with dithiothreitol. The equilibrium dissociation constant for reversible binding to the AVP by Sp-NONOate, or Ki, was 0.47 mM, and the first-order rate constant for irreversible inhibition of the AVP by Sp-NONOate, or ki, was 0.0036 s(-1). Two hallmarks of a successful adenovirus infection were abolished by the NO donors: the appearance of E1A protein and the cleavage of cytokeratin 18 by AVP. Treatment of infectious virus by DEA-NONOate dramatically decreased viral infectivity. These data suggest that NO may be a useful antiviral agent against viruses encoding a cysteine proteinase and in particular may be an antiadenovirus agent.
一氧化氮（NO）是先天性免疫系统的一种抗病毒效应物，但NO的病毒靶点鲜有被确定的。我们现在表明，NO通过靶向腺病毒蛋白酶（AVP）来抑制腺病毒复制。由二乙胺NONOate（DEA-NONOate）或精胺NONOate（Sp-NONOate）产生的NO抑制了AVP。用二硫苏糖醇可使抑制作用逆转。Sp-NONOate与AVP可逆结合的平衡解离常数（即Ki）为0.47 mM，Sp-NONOate对AVP不可逆抑制的一级速率常数（即ki）为0.0036 s(-1)。NO供体消除了腺病毒成功感染的两个标志：E1A蛋白的出现以及AVP对细胞角蛋白18的切割。用DEA-NONOate处理感染性病毒可显著降低病毒感染性。这些数据表明，NO可能是一种针对编码半胱氨酸蛋白酶的病毒的有用抗病毒剂，尤其可能是一种抗腺病毒剂。
