A small molecule inhibitor of HSV genital infections

HSV 生殖器感染的小分子抑制剂

• 批准号: 9763444
• 负责人: DEEPAK SHUKLA
• 金额: $ 39.98万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763444
• 关键词: Acute; Acyclovir; Adult; Affect; Afferent Neurons; Africa South of the Sahara; Age-Years; Antiviral Agents; Antiviral Therapy; Autophagocytosis; Behavioral; Biological Assay; Cardiovascular system; Cell Cycle; Chemical Structure; Chemicals; Chronic; Clinical Research; Clinical Trials; Complex; Data; Development; Disease; Drug resistance; Exhibits; Female; Formulation; Future; Genetic Transcription; Genital system; Genome; Goals; HIV; Health; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Human; Human Herpesvirus 2; Immune; Immunocompromised Host; Immunohistochemistry; In Situ Hybridization; Incidence; Infection; Knowledge; Lesion; Mediating; Mitotic Spindle Apparatus; Modeling; Molecular; Mus; Nuclear; Nuclear Translocation; Oral; Pain; Pharmaceutical Preparations; Phosphorylation; Plaque Assay; Population; Prevention; Prevention strategy; Preventive treatment; Pyrrolidines; Recurrence; Reporting; Resistance; Resistance development; Sensory Ganglia; Serum; Sexually Transmitted Diseases; Simplexvirus; Solid; TANK-binding kinase 1; Testing; Thiophenes; Tissues; Topical application; Toxic effect; Transcript; Treatment Cost; Treatment Efficacy; Treatment Side Effects; Ulcer; Vaccines; Viral; Woman; World Health Organization; alternative treatment; analog; base; clinical efficacy; cofactor; cytokine; effective therapy; experimental study; genital herpes; genital infection; improved; in vivo; inhibitor/antagonist; innovation; mouse model; mutant; neurotropic; nucleoside analog; preclinical efficacy; preclinical study; prevent; sexually active; small molecule; small molecule inhibitor; symptom treatment; topical antiviral; transmission process; treatment duration; treatment strategy

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.

摘要 生殖器疱疹是一种由单纯疱疹病毒2型（HSV-2）引起的性传播疾病。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 由于受到单纯疱疹病毒-2型感染的困扰，过去几年单纯疱疹病毒-1型生殖器感染病例显着增加 几十年这造成了一个复杂的健康问题，因为更高比例的成年人可能携带HSV-1。HSV 属于嗜神经性疱疹病毒的一个亚科，其在感觉神经元中建立潜伏期并引起终身的 反复感染。目前针对生殖器疱疹的一线治疗包括阿昔洛韦（ACV）及其 类似物虽然在过去的几十年里，这些方法被证明是有效的，但与这些方法相关的局限性仍然存在。 抗病毒药物如：a）增加耐药性的发生率，特别是在免疫功能低下的患者中， B）作为局部制剂的有限功效，和c）与长期给药相关的更高的治疗成本和副作用。 术语系统治疗，限制其使用，并强调需要新的和改进的治疗方案。 本研究的重点是评估小分子药物Iazovir（IZV）作为一种可行的替代药物的疗效 生殖器疱疹的治疗方法我们有强大的和支持的初步数据，以发展IZV作为一个全新的 一类高效的抗病毒药物。提出了两个具体目标，以确定功效并提供 IZV抗病毒作用背后的分子机制。目标1将侧重于确定 IZV的抗病毒作用。基于我们有趣的初步结果，IZV减少了HSV基因组， 转录水平，我们假设IZV可以：（i）通过TANK结合阻断HSV-2基因组的转录 激酶1（TBK 1）介导的NF-κ B B活化的调节和（ii）通过其抑制HSV-2复制 对核有丝分裂器（NuMA）的抑制活性。计划进行多项实验来测试我们的 假说.平行地，将产生IZV抗性HSV-2突变体，以提供无偏见和更深入的研究。 了解IZV的抗病毒潜力的机制。Aim 2将使用小鼠模型， 生殖器HSV-2感染，以确定作为局部和口服治疗的IZV治疗的体内临床前功效。 抗病毒治疗还将进行实验，以证明IZV作为口服治疗的高效性 抗由HSV-1引起的鼠生殖器感染。我们还将确定急性和慢性毒性 通过IZV治疗诱导，以充分表征其临床前疗效。成功完成我们的 研究将确立IZV作为一类新的HSV抗病毒药物，为未来的临床试验和研究做好准备。