Development of Novel Therapeutic Agents for Norovirus Infection

描述（由申请人提供）：诺如病毒（NIAID B 类优先病原体）是食源性或水源性胃肠炎爆发的主要原因，估计每年在美国造成 2300 万例病例。然而，目前还没有商业化的针对诺如病毒的疫苗或抗病毒药物。我们启动了一项全面计划，旨在与各个研究所的药物化学家和病毒学家合作开发抗诺如病毒疗法。使用一种新型的基于细胞的诺瓦克病毒（NV）复制系统，我们确定了病毒蛋白酶（Pro）和细胞酰基辅酶轴甾醇酰基转移酶（ACAT）作为潜在的治疗靶点，并进一步证明两类化合物可能分别通过抑制病毒Pro和ACAT而显着减少病毒复制。由于 NV Pro 和 ACAT 在病毒复制中发挥着关键作用，因此提出了这样的假设：能够选择性抑制这些酶的药物具有潜在的治疗价值。因此，该计划的长期目标是通过在向 FDA 提交 IND 申请之前的阶段推进活性化合物，开发针对人类诺如病毒的新型小分子疗法。我们制定了以下具体目标，将我们的热门化合物推进为临床前开发的候选药物。具体目标 1：利用药物/组合化学和分子建模来优化两类化合物。该目标的目的是确定满足效力、选择性、c log P、生物利用度和其他药物开发相关参数的先导化合物。目标 2. 进行体外研究以确定两类化合物的作用机制。我们还将通过长期治疗来评估病毒对先导化合物的耐药性。目标 3. 进行 ADME/TOX 和口服生物利用度研究，以优化选定先导化合物的药代动力学参数。目标 4. 使用人类诺如病毒感染的无菌猪模型证明先导化合物的体内功效。这些具体目标的实现将为开展 IND 支持研究奠定基础，包括先导化合物的大规模 GMP 合成、药代动力学、GLP 毒理学和安全药理学。相关性（参见说明）：人类诺如病毒现在是食物或水源性胃肠炎疾病的主要原因，但目前还没有针对它们的市售疫苗或抗病毒药物。我们的研究旨在将我们的热门化合物推进为临床前开发的候选药物，这将对诺如病毒研究和公共卫生产生重大影响。

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.