Development of Novel Therapeutic Agents for Norovirus Infection

诺如病毒感染新型治疗药物的开发

• 批准号: 7642940
• 负责人: Kyeong-Ok Chang
• 金额: $ 101.78万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642940
• 关键词: Acyltransferase; Animal Model; Antiviral Agents; Biological Availability; Categories; Cells; Coenzymes; Cytochrome P450; Development; Disease Outbreaks; Drug Kinetics; Enzymes; Family suidae; Food; Gastroenteritis; Gnotobiotic; Goals; Housing; Human; In Vitro; Infection; Institutes; Instruction; Lead; Libraries; Modeling; Molecular Models; National Institute of Allergy and Infectious Disease; Norovirus; Norwalk virus; Oral; Peptide Hydrolases; Permeability; Pharmacology; Play; Replicon; Role; Safety; Screening procedure; Series; Staging; System; Therapeutic; Therapeutic Agents; Toxicology; Vaccines; Viral; Viral Proteins; Virus Replication; Water; base; combinatorial chemistry; cytotoxicity; drug candidate; drug development; in vivo; meetings; molecular modeling; novel; novel therapeutics; pathogen; pre-clinical; programs; public health research; small molecule; therapeutic target; viral RNA; viral resistance

DESCRIPTION (provided by applicant): Noroviruses (NIAID category B priority pathogens) are a leading cause of food- or water-borne gastroenteritis outbreaks, responsible for an estimated 23 million cases annually in the US. However, currently there are no commercially available vaccines or antivirals against noroviruses. We have initiated a comprehensive plan aimed at developing anti-noroviral therapeutics in cooperation with medicinal chemists and virologists from various institutes. Using a novel cell-based Norwalk virus (NV) replication system, we have identified viral proteinase (Pro) and cellular acyl-coenzyme Axholesterol acyltransferase (ACAT) as potential therapeutic targets and have furthermore demonstrated that two classes of compounds significantly reduced virus replication, presumably via the inhibition of viral Pro and ACAT, respectively. Since NV Pro and ACAT play a critical role in viral replication, the hypothesis is advanced that agents capable of inhibiting these enzymes selectively are of potential therapeutic value. Thus, the long term goal of this program is the development of novel small molecule therapeutics against human noroviruses by advancing the active compounds through the stage prior to filing an IND application with the FDA. We have established the following specific aims for advancing our hit compounds into a drug candidate for preclinical development. Specific Aim 1: Utilize medicinal/combinatorial chemistry and molecular modeling to optimize two classes of compounds. The goal of this aim is to identify lead compounds that meet potency, selectivity, c log P, bioavailability, and other relevant parameters for drug development. Aim 2. Conduct in vitro studies to establish the mechanism of action of two classes of compounds. We will also evaluate viral resistance to lead compounds by long-term treatment. Aim 3. Conduct ADME/TOX and oral bioavailability studies to optimize the phamacokinetic parameters of selected lead compounds. Aim 4. Demonstrate in vivo efficacy of lead compounds using the gnotobiotic pig model of human norovirus infection. Accomplishment of these specific aims will set the stage for conducting IND-enabling studies, including large-scale GMP synthesis of lead compounds, pharmacokinetics, GLP toxicology and safety pharmacology. RELEVANCE (See instructions): Human noroviruses are now the leading cause of food- or water-borne gastroenteritis illnesses, but currently there are no commercially available vaccines or antivirals against them. Our studies aim at advancing our hit compounds into a drug candidate for preclinical development, which will have a significant impact on norovirus research and public health.

描述（由申请人提供）：诺病毒（NIAID类别B优先病原体）是食品或水传播胃肠炎爆发的主要原因，估计每年在美国估计有2300万例病例。但是，目前尚无针对诺病毒的市售疫苗或抗病毒药。我们启动了一项旨在与来自各种研究所的药物化学家和病毒学家合作开发抗新病毒治疗剂的综合计划。 Using a novel cell-based Norwalk virus (NV) replication system, we have identified viral proteinase (Pro) and cellular acyl-coenzyme Axholesterol acyltransferase (ACAT) as potential therapeutic targets and have furthermore demonstrated that two classes of compounds significantly reduced virus replication, presumably via the inhibition of viral Pro and ACAT, respectively.由于NV Pro和ACAT在病毒复制中起着关键作用，因此假设能够选择性抑制这些酶具有潜在的治疗价值。因此，该程序的长期目标是通过在向FDA提交IND应用之前通过阶段推进活性化合物来开发针对人类诺病毒的新型小分子疗法。我们已经建立了以下特定目标，将我们的热门化合物推广到临床前开发的候选药物中。特定目标1：利用药用/组合化学和分子建模来优化两类化合物。此目的的目的是确定符合效力，选择性，C log P，生物利用度和其他相关参数的铅化合物。目标2。进行体外研究以建立两类化合物的作用机理。我们还将通过长期治疗评估病毒耐药性对铅化合物的抗性。 AIM 3。进行ADME/TOX和口服生物利用度研究，以优化选定铅化合物的Phamacokinetic参数。 AIM 4。使用人诺如病毒感染的gnotobiotic猪模型证明铅化合物的体内功效。这些特定目标的完成将为进行辅助研究奠定阶段，包括大规模的GMP合成铅化合物，药代动力学，GLP毒理学和安全药理学。相关性（请参阅说明）：人类诺如病毒现在是食物或水源性胃炎疾病的主要原因，但目前尚无针对它们的市售疫苗或抗病毒药。我们的研究旨在将热门化合物推进到临床前开发的药物候选者，这将对诺如病毒研究和公共卫生产生重大影响。