COVID-19: SARS-CoV-2 Neutralizing Agents

COVID-19：SARS-CoV-2 中和剂

• 批准号: 10375433
• 负责人: SUBHRA MOHAPATRA
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375433
• 关键词: 2019-nCoV; 3-Dimensional; ACE2; Acute Respiratory Distress Syndrome; Address; Biological; Biological Assay; Blood-Air Barrier; COVID-19; COVID-19 pandemic; COVID-19 pandemic effects; COVID-19 patient; COVID-19 treatment; Cell Culture Techniques; Cell model; Cells; Cessation of life; Chemicals; Chitosan; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Country; Coxsackie Viruses; Data; Diagnosis; Disease; Docking; Effectiveness; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Evolution; FDA approved; Family; Fibroblasts; Friends; Future; HIV; Hand; Human; In Vitro; Individual; Infection; Infection Control; Influenza; Lead; Lung; Measures; Methods; Modeling; Molecular; Oxygen; Oxygen Therapy Care; Patients; Pharmaceutical Preparations; Prevention; Preventive vaccine; Prophylactic treatment; RNA Viruses; Regimen; Research; Respiratory syncytial virus; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; SARS-CoV-2 spike protein; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Vaccines; Viral; Viral Load result; Viral Physiology; Virus; Virus Diseases; Work; alveolar epithelium; base; crosslink; dietary supplements; efficacy evaluation; efficacy testing; immunocytochemistry; improved; in vivo; innovation; mouse model; nanomedicine; nanoscale; novel coronavirus; novel virus; overexpression; pandemic disease; particle; prophylactic; remdesivir; response; tripolyphosphate

COVID-19 super pandemic is still suffering from the lack of a vaccine or infection control measures and the lack of any treatments against this new virus. One of the unique features of SARS-CoV-2 is that it has an R0=2.2 (the ability of an infected patient to spread the disease) vs R0=1 for SARS-CoV and R0=0.3 for Influenza. Due to this, individuals infected with SARS-CoV-2 remain asymptomatic and yet pass on the virus to family, friends and colleagues at work, thus expanding the COVID-19 cases. Given the impending second wave of the pandemic and the potential of SARS-CoV-2 being a seasonal virus, there is a dire urgent need to develop prophylactic vaccines and/or therapy (PV/T), which can treat the viral infection during the virus expansion in the lung and during oxygen therapy. This proposal addresses the COVID-19 pandemic by developing a PV/T, which will be a unique approach that has not been tested before. This project is inspired by discovery of a special agent, i.e., a nanoscale 10 kDa chitosan, derived using proprietary methods from chitosan used as a common diet supplement [‘generally regarded as safe’ (GRAS) by FDA] , referred to as nanoscale chitosan derivative (NCD). NCD1 and other chemical derivatives were synthesized and tested for their anti-viral activity by neutralizing RNA of viruses, such as HIV, respiratory syncytial virus (RSV) and Coxsackie virus. Thus, in preliminary studies, 5 out of 9 examined showed significant anti-viral (80-90%) effects. Further, molecular docking studies showed that NCD1 can dock to the Spike protein of SARS-CoV-2 virus. Finally, we have developed lung targeted nanomedicine methods to combine NCD1 with remdesivir for improving treatment efficacy and expanding its use for prevention. Based on data at hand, it is hypothesized that NCDs by themselves or in combination with remdesivir will provide an excellent PV/T against COVID-19. To test this hypothesis, it is planned to examine in both prophylactic and therapeutic settings: the antiviral effectiveness of NCDs in vitro lung epithelial cell cultures (aim #1), the effectiveness of select top two NCDs with or without remdesivir in EpiAlveolar 3D co-culture model (MatTek) of the air-blood barrier (aim #2), and efficacy of select NCD with or without remdesivir in in vivo mouse models (aim #3). The results will provide us in identifying one or two NCDs as a single agent or in combination with remdesivir as COVID-19 PV/T regimen(s), which will inhibit SARS-CoV-2 infection. The results of these studies will uniquely contribute to the repertoire of COVID-19 prophylactics and therapeutics and allow us to move towards regulatory approval and future clinical trials. The team is uniquely poised to conduct these studies and has appropriate expertise. The successful completion of the proposed research is expected to lead to obtaining regulatory approval for a clinical trial.

由于缺乏疫苗或感染控制措施，COVID-19 超级大流行仍在继续 SARS-CoV-2 的独特特征之一是缺乏针对这种新病毒的任何治疗方法。 它的 R0=2.2（受感染患者传播疾病的能力）与 SARS-CoV 的 R0=1 对于流感，R0=0.3 因此，感染 SARS-CoV-2 的个体仍然无症状。 但却将病毒传染给家人、朋友和同事，从而扩大了 COVID-19 的传播范围 鉴于第二波大流行即将到来以及 SARS-CoV-2 的潜力。 一种季节性病毒，迫切需要开发预防性疫苗和/或疗法（PV/T）， 它可以治疗病毒在肺部扩张期间和氧疗期间的病毒感染。 该提案通过开发 PV/T 来应对 COVID-19 大流行，这将是一个独特的方案 该项目的灵感来自于一种特殊药剂的发现， 即纳米级 10 kDa 壳聚糖，采用专有方法从用作 常见的膳食补充剂[FDA“普遍认为安全”(GRAS)] , 称为纳米级 合成并测试了壳聚糖衍生物（NCD1）和其他化学衍生物。 通过中和病毒 RNA 来发挥抗病毒活性，例如 HIV、呼吸道合胞病毒 (RSV) 因此，在初步研究中，9 种病毒中有 5 种表现出显着的抗病毒作用。 (80-90%) 效应此外，分子对接研究表明 NCD1 可以与 Spike 对接。 最后，我们开发了针对肺部的纳米医学方法。 将 NCD1 与瑞德西韦联合使用可提高治疗效果并扩大其预防用途。 根据现有数据，率先将非传染性疾病单独治疗或与瑞德西韦联合治疗 将提供针对 COVID-19 的出色 PV/T。为了检验这一假设，计划在 2019 年进行检验。 预防和治疗环境：非传染性疾病体外肺上皮细胞的抗病毒效果 细胞培养（目标#1），选择前两种非传染性疾病（使用或不使用瑞德西韦）的有效性 气血屏障的 EpiAlveolar 3D 共培养模型 (MatTek)（目标 #2）以及选择的功效 在体内小鼠模型中使用或不使用瑞德西韦的非传染性疾病（目标#3）。 结果将为我们提供 识别一种或两种非传染性疾病作为单一药物或与瑞德西韦联合作为 COVID-19 PV/T 这些研究的结果将是独一无二的。 为 COVID-19 预防和治疗方案做出贡献，让我们能够行动起来 该团队为开展这些工作做好了独特的准备。 研究并具有适当的专业知识成功完成拟议的研究。 预计将获得临床试验的监管批准。