A small molecule inhibitor of HSV genital infections

摘要 生殖器疱疹是一种性传播疾病，主要由单纯疱疹病毒2型(HSV-2)引起。一个 据估计，美国有20%的人口感染了HSV-2。增加了问题和疾病 受HSV-2感染的困扰，生殖器感染HSV-1的病例在过去几年里大幅上升 几十年。这造成了一个复杂的健康问题，因为成年人中携带HSV-1的比例要高得多。单纯疱疹病毒 属于嗜神经性疱疹病毒的一个亚家族，它在感觉神经元中建立潜伏期并导致终生 反复感染。目前治疗生殖器疱疹的一线药物包括阿昔洛韦(ACV)及其 类比。虽然这些措施在过去的几十年里被证明是有效的，但与这些措施相关的限制 抗病毒药物如：a)耐药性发生率增加，特别是在免疫功能低下的患者中， B)作为局部制剂的疗效有限，以及c)较高的治疗费用和与长期药物相关的副作用。 系统治疗的术语，限制其使用，并强调需要新的和改进的治疗选择。 这项研究的重点是评估作为可行替代品的小分子Iazovir(IZV)的疗效。 生殖器疱疹的治疗。我们有强有力的初步数据支持将IZV发展为一个全新的 一类高效的抗病毒药物。提出了两个具体的目标，这将建立有效性并提供 IZV抗病毒作用的分子机制。目标1将集中于确定 IZV的抗病毒作用。根据我们有趣的初步结果，IZV既减少了HSV基因组，又降低了HSV基因组 转录水平，我们假设IZV可以：(I)通过TANK结合阻止HSV-2基因组的转录 蛋白激酶1(Tbk1)介导的核因子-单纯疱疹病毒B(NF-B)活性的调节，以及(Ii)通过其 对核有丝分裂装置(NUMA)的抑制活性。计划进行多项实验来测试我们的 假设。同时，将产生抗IZV的HSV-2突变体，以提供无偏见和更深的 了解控制IZV抗病毒潜力的机制。Aim 2将使用鼠标模型 生殖器单纯疱疹病毒2型感染作为外用和口服IZV治疗的体内临床前疗效 抗病毒治疗。还将进行实验，以证明IZV作为一种口服治疗的高效性 对抗由HSV-1引起的小鼠生殖器感染。我们还将确定急性和慢性毒性 用IZV治疗诱导，以充分表征其临床前疗效。成功完成我们的 研究将使IZV成为一种新的HSV抗病毒药物，为未来的临床试验和研究做好准备。

Abstract Genital herpes is a sexually transmitted disease primarily caused by herpes simplex virus type 2 (HSV-2). An estimated 20% of the population in the US is infected with HSV-2. Adding to the problems and diseases afflicted by HSV-2 infections, cases of genital infections by HSV-1 have gone up significantly in the past few decades. This creates a complex health issue since much higher percentages of adults may harbor HSV-1. HSV belongs to a subfamily of neurotropic herpesviruses that establish latency in sensory neurons and cause lifelong recurrent infections. Current frontline treatments against genital herpes include acyclovir (ACV) and its analogs. While these have proven effective over the past few decades, the limitations associated with these antivirals such as: a) increasing incidences of drug resistance especially among immunocompromised patients, b) limited efficacy as topical formulations, and c) higher cost of treatment and side effects associated with long- term systemic treatments, restrict their use and underscore the need for new and improved treatment options. The focus of this study is to evaluate the efficacy of a small molecule, Iazovir (IZV), as a viable alternative treatment for genital herpes. We have strong and supportive preliminary data to develop IZV as a brand new class of highly effective antivirals. Two specific aims are proposed that will establish the efficacy and provide the molecular mechanism behind the antiviral action of IZV. Aim 1 will focus on determining the mechanism of antiviral action by IZV. Based on our interesting preliminary results that IZV reduces both HSV genome and transcript levels, we hypothesize that IZV can: (i) block transcription of HSV-2 genomes by TANK binding kinase 1 (TBK1)-mediated modulation of NF-B activation and (ii) inhibit HSV-2 replication through its suppressive activity on nuclear mitotic apparatus (NuMA). Multiple experiments are planned to test our hypothesis. In parallel, IZV resistant HSV-2 mutants will be generated to provide an unbiased and deeper understanding of the mechanisms that govern the antiviral potential of IZV. Aim 2 will use mouse models of genital HSV-2 infection to determine the in vivo preclinical efficacy of IZV treatment as a topical and oral antiviral therapy. Experiments will also be undertaken to demonstrate IZV’s high efficacy as an oral treatment against murine genital infections caused by HSV-1. We will also determine the acute and chronic toxicities induced by IZV treatment in order to fully characterize its pre-clinical efficacy. Successful completion of our studies will establish IZV as a new class of HSV antivirals ready for future clinical trials and studies.