Cdk inhibitors: novel antivirals for VZV

描述(由申请人提供)：免疫受损的人是由水痘带状疱疹病毒(VZV)重新激活引起的带状疱疹的高风险人群。持久的疼痛、视力丧失、脑炎、播散、复发和持续性导致艾滋病患者的显著发病率，并极大地影响他们的生活质量。目前阿昔洛韦及其衍生物的治疗已经取得了一些成功，但尽管进行了治疗，疼痛和其他后遗症往往仍然存在。研究阻止HZ病变扩散的新疗法可能会减少并发症的痛苦，这些并发症继续给艾滋病患者、他们的照顾者和社会带来负担。一种防止VZV复制的新方法是用抑制细胞周期蛋白依赖性激酶的化合物处理宿主细胞，导致细胞周期停滞并阻止VZV的生长。主要的假设是VZV的复制依赖于细胞和/或病毒激酶的活性，而细胞和/或病毒激酶是CDK抑制剂的靶标。这项建议的目的是在细胞模型和VZV复制的动物模型中测试药物的抗病毒效果，并最终描述CDK抑制剂药物使细胞不允许复制VZV的机制。第一个目的是评估CDK抑制剂在体外阻断VZV复制的能力。罗斯科维汀、紫杉醇和黄烷醇是导致细胞周期停滞的三种cdk抑制剂，将测试它们在细胞培养中阻止VZV生长的能力。第二个目的是评估CDK抑制剂在体内阻断VZV复制的能力。人皮肤外植体和植入人皮肤或胸腺/肝脏组织(T细胞的来源)的SCID-HU小鼠将被用来研究CDK抑制剂对VZV复制的影响。第三个目的是确定CDK抑制VZV复制的分子机制。我们将研究VZV感染对细胞周期调节成分的影响，并确定参与这些相互作用的蛋白质。这项建议旨在从分子水平探讨CDK抑制剂如何在体外和体内阻止VZV复制。准确了解CDK抑制剂如何阻止VZV生长是开发有效抗病毒药物的起点。

DESCRIPTION (provided by applicant): Immunocompromised individuals are at high risk for herpes zoster caused by reactivation of varicella zoster virus (VZV). Long-lasting pain, vision loss, encephalitis, dissemination, recurrence and persistence cause significant morbidity in AIDS patients and greatly impact their quality of life. Current treatments with acyclovir and its derivatives have met with some success, but pain and other sequelae often persist despite therapy. Research into new treatments that stop the spread of HZ lesions may reduce the suffering from complications that continue to place a burden on AIDS patients, their caregivers, and on society. A novel approach to preventing VZV replication is to treat the host cell with compounds that inhibit cyclin-dependent kinases, causing cell cycle arrest and blocking VZV growth. The primary hypothesis is that VZV replication is dependent on the activity of cellular and/or viral kinases that are targets of cdk inhibitors. The goals of this proposal are to test the antiviral effects of the drugs in cell models and in an animal model of VZV replication and ultimately describe the mechanisms whereby cdk inhibitor drugs render cells nonpermissive for VZV replication. The first aim is to evaluate the ability of cdk inhibitors to block VZV replication in vitro. Roscovitine, purvalanol, and flavopiridol are three cdk inhibitors that cause cell-cycle arrest and will be tested for their ability to block VZV growth in cell culture. The second aim is to evaluate the ability of cdk inhibitors to block VZV replication in vivo. Human skin explants and the SCID-hu mouse implanted with human skin or thymus/liver tissues (a source of T cells) will be used to study the effects of cdk inhibitors on VZV replication. The third aim is to define the molecular mechanisms of cdk inhibition of VZV replication. The effects of VZV infection on cell cycle regulatory components will be studied and the proteins involved in these interactions will be identified. This proposal is designed to address at the molecular level how cdk inhibitors prevent VZV replication in vitro and in vivo. Understanding precisely how cdk inhibitors block VZV growth is the starting point for development of effective antiviral agents.