Schang Luis M, Bantly Andrew, Knockaert Marie, Shaheen Farida, Meijer Laurent, Malim Michael H, Gray Nathanael S, Schaffer Priscilla A
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
J Virol. 2002 Aug;76(15):7874-82. doi: 10.1128/jvi.76.15.7874-7882.2002.
Pharmacological cyclin-dependent kinase (cdk) inhibitors (PCIs) block replication of several viruses, including herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus type 1 (HIV-1). Yet, these antiviral effects could result from inhibition of either cellular cdks or viral enzymes. For example, in addition to cellular cdks, PCIs could inhibit any of the herpesvirus-encoded kinases, DNA replication proteins, or proteins involved in nucleotide metabolism. To address this issue, we asked whether purine-derived PCIs (P-PCIs) inhibit HSV and HIV-1 replication by targeting cellular or viral proteins. P-PCIs inhibited replication of HSV-1 and -2 and HIV-1, which require cellular cdks to replicate, but not vaccinia virus or lymphocytic choriomeningitis virus, which are not known to require cdks to replicate. P-PCIs also inhibited strains of HSV-1 and HIV-1 that are resistant to conventional antiviral drugs, which target viral proteins. In addition, the anti-HSV effects of P-PCIs and a conventional antiherpesvirus drug, acyclovir, were additive, demonstrating that the two drugs act by distinct mechanisms. Lastly, the spectrum of proteins that bound to P-PCIs in extracts of mock- and HSV-infected cells was the same. Based on these observations, we conclude that P-PCIs inhibit virus replication by targeting cellular, not viral, proteins.
药理学上的细胞周期蛋白依赖性激酶（cdk）抑制剂（PCIs）可阻断包括1型单纯疱疹病毒（HSV-1）和1型人类免疫缺陷病毒（HIV-1）在内的多种病毒的复制。然而，这些抗病毒作用可能是由于抑制细胞cdk或病毒酶所致。例如，除了细胞cdk外，PCIs还可抑制任何疱疹病毒编码的激酶、DNA复制蛋白或参与核苷酸代谢的蛋白。为了解决这个问题，我们研究了嘌呤衍生的PCIs（P-PCIs）是否通过靶向细胞或病毒蛋白来抑制HSV和HIV-1的复制。P-PCIs抑制需要细胞cdk进行复制的HSV-1和-2以及HIV-1的复制，但不抑制已知不需要cdk进行复制的痘苗病毒或淋巴细胞性脉络丛脑膜炎病毒。P-PCIs还抑制了对靶向病毒蛋白的传统抗病毒药物耐药的HSV-1和HIV-1毒株。此外，P-PCIs和传统抗疱疹病毒药物阿昔洛韦的抗HSV作用是相加的，这表明这两种药物的作用机制不同。最后，在未感染和HSV感染细胞提取物中与P-PCIs结合的蛋白质谱是相同的。基于这些观察结果，我们得出结论，P-PCIs通过靶向细胞而非病毒蛋白来抑制病毒复制。
