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A small molecule inhibitor of HSV genital infections

HSV 生殖器感染的小分子抑制剂

基本信息

批准号：
10205994
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
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-14 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205994
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 Genitalia Genome Goals HIV Health Herpesviridae Herpesviridae Infections Herpesvirus 1 Human Human Herpesvirus 2 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 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 efficacy evaluation experimental study genital herpes genital infection improved in vivo inhibitor/antagonist innate immune sensing innovation mouse model mutant neurotropic nucleoside analog preclinical efficacy preclinical study prevent recurrent infection sexually active small molecule small molecule inhibitor symptom treatment topical antiviral transmission process treatment duration treatment strategy

项目摘要

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