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.

抽象的 生殖器疱疹是一种性传播疾病，主要由 2 型单纯疱疹病毒 (HSV-2) 引起。一个 据估计，美国有 20% 的人口感染了 HSV-2。增加问题和疾病 受HSV-2感染困扰，过去几年HSV-1生殖器感染病例显着增加 几十年。这会造成复杂的健康问题，因为成年人中可能携带 HSV-1 的比例要高得多。单纯疱疹病毒 属于嗜神经疱疹病毒的一个亚科，在感觉神经元中建立潜伏期并导致终生 反复感染。目前针对生殖器疱疹的一线治疗方法包括阿昔洛韦 (ACV) 及其 类似物。虽然这些在过去几十年中被证明是有效的，但与这些相关的局限性 抗病毒药物，例如：a）耐药性发生率增加，特别是在免疫功能低下的患者中， b) 作为局部制剂的功效有限，以及 c) 治疗成本较高，且与长期用药相关的副作用较高。 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 Iazovir (IZV) 作为可行替代品的功效 治疗生殖器疱疹。我们拥有强有力的初步数据支持将 IZV 开发为全新的 一类高效抗病毒药物。提出了两个具体目标，即确定功效并提供 IZV 抗病毒作用背后的分子机制。目标 1 将重点确定机制 IZV 的抗病毒作用。根据我们有趣的初步结果，IZV 会减少 HSV 基因组，并且 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 (TBK1) 介导的 NF-κB 激活调节，以及 (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 假设。与此同时，将产生 IZV 抗性 HSV-2 突变体，以提供公正且更深入的研究 了解控制 IZV 抗病毒潜力的机制。目标 2 将使用以下鼠标模型 生殖器 HSV-2 感染，以确定 IZV 治疗作为局部和口服治疗的体内临床前疗效 抗病毒治疗。还将进行实验来证明 IZV 作为口服治疗的高效能 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 IZV 治疗诱导，以充分表征其临床前疗效。顺利完成我们的 研究将把 IZV 确定为一类新的 HSV 抗病毒药物，为未来的临床试验和研究做好准备。