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)是食物或水传播的胃肠炎暴发的主要原因，据估计美国每年有2300万例。然而，目前还没有针对诺如病毒的商业疫苗或抗病毒药物。我们启动了一项全面计划，旨在与各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。利用一种新的基于细胞的诺瓦克病毒(NV)复制系统，我们已经确定病毒蛋白水解酶(Pro)和细胞酰基辅酶Axholestol ACAT(ACAT)是潜在的治疗靶点，并进一步证明两类化合物显著抑制病毒复制，可能分别是通过抑制病毒Pro和ACAT。由于NV Pro和ACAT在病毒复制中起着关键作用，提出了一种假设，即能够选择性地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申请之前推进活性化合物的阶段，开发针对人类诺如病毒的新型小分子疗法。我们已经确定了以下具体目标，以推动我们的Hit化合物成为临床前开发的候选药物。具体目标1：利用药物/组合化学和分子模拟优化两类化合物。这一目标的目的是确定满足药效、选择性、clogP、生物利用度和其他药物开发相关参数的先导化合物。目的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铅化合物的耐药性。目的3.进行ADME/TOX和口服生物利用度研究，优化所选先导化合物的药动学参数。目的4.利用诺如病毒感染猪的动物模型，验证先导化合物的体内药效。这些具体目标的实现将为开展支持IND的研究奠定基础，包括铅化合物的大规模GMP合成、药代动力学、GLP毒理学和安全药理学。相关性(见说明)：人类诺如病毒现在是食物或水传播的胃肠炎疾病的主要原因，但目前还没有针对它们的商业疫苗或抗病毒药物。我们的研究旨在推动我们的热门化合物成为临床前开发的候选药物，这将对诺沃克病毒的研究和公众健康产生重大影响。

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.