Anti-norovirus protease inhibitors for immunocompromised patients

用于免疫功能低下患者的抗诺如病毒蛋白酶抑制剂

• 批准号: 10567754
• 负责人: LADISLAU Christopher KOVARI
• 金额: $ 79.62万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-11 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567754
• 关键词: 3-Dimensional; Acute; Antiviral Agents; Benchmarking; Binding; Biocompatible Materials; Biological Assay; Biological Availability; Calicivirus; Category B pathogen; Cells; Cessation of life; Characteristics; Child; Chronic; Complex; Coronavirus; Crystallography; Data; Disease model; Drug Efflux; Drug Targeting; Drug resistance; Elderly; Emerging Communicable Diseases; Enterovirus; Enzyme Kinetics; Enzymes; FDA approved; Face; Family; Gastroenteritis; Goals; HIV-1; Half-Life; Health Care Costs; Hepatitis C virus; Hospitalization; Human; Immunocompromised Host; Infection; Intervention; Intestines; Investigational New Drug Application; Lead; Libraries; Life; Liver; Liver Microsomes; Medical; Modeling; Morbidity - disease rate; Mus; National Institute of Allergy and Infectious Disease; Norovirus; Nucleosides; Oral; Outcome; Pathology; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Polyproteins; Population; Prevention; Prevention approach; Production; Protease Inhibitor; Public Health; Recombinant Proteins; Replicon; Research; Resistance; Resolution; Risk; Role; Series; Solubility; Speed; Structure; System; Testing; Therapeutic Index; Transplant Recipients; United States; United States National Institutes of Health; Vaccines; Valine; Viral; Viral Gastroenteritis; Viral Proteins; Virus Replication; ZIKA; analog; anti-viral efficacy; antiviral drug development; aqueous; chronic infection; congenital immunodeficiency; cytotoxicity; design; drug candidate; drug efficacy; economic cost; efficacy study; efficacy testing; foodborne illness; immunodeficient mouse model; inhibitor; innovation; member; meter; milligram; molecular modeling; mortality; mouse model; nanomolar; nucleoside analog; peptidomimetics; pharmacologic; preclinical study; small molecule; small molecule inhibitor; targeted agent; vaccine development; virology

PROJECT SUMMARY/ABSTRACT Human Noroviruses (hNoV), which belong to the Caliciviridae family, are the leading cause of viral gastroenteritis and food-borne disease worldwide. Each year in the United States alone, hNoV is responsible for greater than 21 million cases of acute gastroenteritis, leading to an estimated 71,000 hospitalizations per year. While most cases resolve within a week, immunocompromised patients, children, and the elderly have an elevated risk of long-term and even fatal infections. Currently, there are no antiviral drugs or vaccines approved for the prevention or treatment of chronic hNoV infections. The main goal of this project is to harness the medical benefits that are offered by the inhibition of viral enzymes, including the hNoV protease. The overall objective of this proposal is to design and develop a protease inhibitor for the treatment of hNoV infections. The hNoV NS6 protease has become an attractive drug target due to its essential role in the viral replication cycle. The central hypothesis is that small-molecule inhibitors targeting the viral protease will limit or eliminate hNoV infections. The rationale for the proposed research is based on our preliminary data, specifically compound 1 and its analogs. These compounds are unique, non-toxic, small peptidomimetic molecules that inhibit NoV replication selectively in culture at 20 nM EC50 by interacting with the hNoV protease. Pharmacological manipulation of the hNoV protease is expected to result in new and innovative approaches to the prevention and treatment of NoV infections. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: Aim 1) To optimize and discover and develop broad-spectrum oral NoV PIs by multiparameter optimization and molecular modeling approaches of lead compounds from our proprietary library. Aim 2) To perform mechanism of action (MOA) and resistance studies of the lead NoV PIs. Aim 3) To evaluate the lead NoV PIs in an immunocompromised mouse model. Under the first aim, about 25 compounds will be designed, synthesized, and tested per year. Under the second aim, enzyme kinetic, crystallographic, host protease inhibition, inhibition of NoV protease production, and drug resistance studies will be performed with the lead compounds. Under the third aim, anti-NoV efficacy studies will be performed in an immunodeficient mouse model. This approach is innovative because we developed a research plan taking full advantage of five recent advances: (1) producing hNoV PR recombinant proteins in milligram amounts; (2) solving the crystal structure of the NoV GII.4 PR - the main drug target; (3) a cell-based hNoV replicon assay; (4) 3D human intestinal enteroid model, and (5) an immunocompromised mouse disease model to study human NoV infection. The proposed research is significant because in-depth pre-clinical studies and characterization of these new peptidomimetics could lead to the approval of the first safe and effective drugs for the treatment of chronic hNoV infections which cause significant morbidity and mortality in immunocompromised patients.

项目概要/摘要 人类诺如病毒 (hNoV) 属于杯状病毒科，是病毒性胃肠炎的主要原因 和全球食源性疾病。每年仅在美国，hNoV 就造成超过 每年有 2,100 万例急性胃肠炎病例，估计导致 71,000 人住院。虽然大多数 病例在一周内痊愈，免疫功能低下的患者、儿童和老年人感染的风险较高 长期甚至致命的感染。目前，尚无批准用于预防的抗病毒药物或疫苗 或治疗慢性hNoV感染。该项目的主要目标是利用以下医疗福利： 通过抑制病毒酶（包括 hNoV 蛋白酶）来提供。该提案的总体目标是 设计和开发用于治疗 hNoV 感染的蛋白酶抑制剂。 hNoV NS6 蛋白酶具有 由于其在病毒复制周期中的重要作用，成为有吸引力的药物靶点。中心假设是 针对病毒蛋白酶的小分子抑制剂将限制或消除 hNoV 感染。理由 拟议的研究基于我们的初步数据，特别是化合物 1 及其类似物。这些 化合物是独特的、无毒的小肽模拟分子，可以选择性地抑制 NoV 复制 通过与 hNoV 蛋白酶相互作用，以 20 nM EC50 进行培养。 hNoV 蛋白酶的药理学操作 预计将产生预防和治疗 NoV 感染的新方法和创新方法。引导 通过强有力的初步数据，该假设将通过追求三个具体目标来检验： 目标 1) 优化和 通过多参数优化和分子建模发现和开发广谱口服 NoV PI 我们专有库中的先导化合物的方法。目标 2) 执行作用机制 (MOA) 和 主要 NoV PI 的耐药性研究。目标 3) 评估免疫受损小鼠中的先导 NoV PI 模型。根据第一个目标，每年将设计、合成和测试约 25 种化合物。下 第二个目标，酶动力学，晶体学，宿主蛋白酶抑制，NoV 蛋白酶产生的抑制， 将对先导化合物进行耐药性研究。第三个目标，抗NoV功效 研究将在免疫缺陷小鼠模型中进行。这种方法是创新的，因为我们 制定了一项研究计划，充分利用五项最新进展：(1) 生产 hNoV PR 重组体 毫克量的蛋白质； (2)解析NoV GII.4 PR——主要药物靶点的晶体结构； （3）一个 基于细胞的 hNoV 复制子测定； (4) 3D 人类肠道肠样模型，以及 (5) 免疫功能低下的小鼠 研究人类NoV感染的疾病模型。拟议的研究意义重大，因为深入的临床前研究 这些新的肽模拟物的研究和表征可能会导致第一个安全且可靠的药物获得批准。 治疗慢性 hNoV 感染的有效药物，该感染导致显着的发病率和死亡率 免疫功能低下的患者。