Targeting polyamines to suppress SARS-CoV-2 related disease

靶向多胺抑制 SARS-CoV-2 相关疾病

基本信息

批准号：
10627308
负责人：
Christian Bime
金额：
$ 15.3万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10627308
关键词：
2019-nCoV ACE2 Acute Respiratory Distress Syndrome Affect Angiotensin Receptor Animal Model Animals Antiviral Response Apoptosis Autoimmune Responses Autophagocytosis Binding COVID-19 COVID-19 pandemic COVID-19 patient COVID-19 severity COVID-19 treatment Cations Cell Culture Techniques Cell Proliferation Cell model Cell physiology Cells Clinical Clinical Trials Collaborations Communicable Diseases Coronavirus DL-alpha-Difluoromethylornithine Diarrhea Disease Disease Outbreaks Dose Drug Combinations Eflornithine Endoplasmic Reticulum Enzymes Epithelial Cells Eukaryotic Cell Evaluation Excretory function FDA approved Gene Expression Genes Genetic Transcription Goals Growth and Development function In Vitro Individual Infection Inflammation Inflammatory Investigation Life Cycle Stages Lower Respiratory Tract Infection Membrane Metabolic Metabolism Middle East Respiratory Syndrome Coronavirus Modeling Mus Names Non-Steroidal Anti-Inflammatory Agents Organ Ornithine Decarboxylase Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase II Clinical Trials Play Polyamine Catabolism Polyamines Preparation Prevention Prevention approach Prokaryotic Cells Research Role SARS coronavirus SARS-CoV-2 infection SARS-CoV-2 pathogenesis Safety Severities Sulindac Testing Therapeutic Viral Viral Physiology Viral Proteins Virus Virus Diseases Virus Replication Work adenoma anti-viral efficacy cancer prevention carcinogenesis cellular targeting colon cancer prevention cytokine disorder prevention drug development efficacy testing endoplasmic reticulum stress extracellular gastrointestinal system high risk in vivo inhibitor mouse model neutrophil novel novel strategies pathogenic virus pharmacologic posttranscriptional protein expression receptor expression relapse prevention respiratory response stool sample translational goal treatment strategy

项目摘要

ABSTRACT The pandemic COronaVIrus disease 2019 (COVID-19) is an infectious disease, which is caused by a novel and highly pathogenic virus strain SARS-CoV-2 (Severe acute respiratory virus syndrome coronavirus 2). The infection may cause severe lower respiratory tract infection with acute respiratory distress and extrapulmonary organ disfunctions in infected individuals. Treatment strategy that both limits SARS-CoV-2 replication and reduce inflammation associated with COVID-19 would provide the greatest therapeutic benefit. Polyamines are naturally occurring organic cations that are essential for growth and development of both prokaryotic and eukaryotic cells. Many viruses require host polyamines for replication in the infected cells and targeting polyamine metabolism during viral infection showed promising results in in vitro and in vivo animal studies. The goal of this proposal is to test the applicability of two currently FDA approved drugs, eflornithine (other name α-difluoromethylornithine or DFMO) and sulindac, and their combination for prevention or treatment of COVID-19 disease. Eftornithine is an irreversible inhibitor of a key polyamine biosynthetic enzyme ornithine decarboxylase (ODC). Sulindac is a common non-steroidal anti-inflammatory drug (NSAIDs), which also induces polyamine catabolism. Eflornithine and sulindac work in a complementary manner to reduce intracellular polyamine levels. The safety doses of eflornithine/sulindac combination have been established for prevention of recurrence of high-risk adenomas (ClinicalTrials.gov Identifier NCT00118365). In this proposal we will test the hypothesis that eflornithine and sulindac combination will reduce both the intracellular polyamine availability for coronavirus replication, and inflammation associated with COVID-19. We will test this hypothesis using cell culture models (Specific Aim 1) and mouse models of COVID-19 disease (Specific Aim 2). Planning activities in preparation for clinical trials for eflornithine/sulindac combination for antiviral indication in collaboration with Cancer Prevention Pharmaceuticals (CPP) (www.canprevent.com) are also included. The translational goal of this project is to develop the effective approach for prevention COVID-19 infection as well as decreasing severity of the viral infection in the COVID-19 patients. It is essential to develop new approaches to prevention and treatment of virus outbreaks.

抽象的大流行的 2019 年冠状病毒病 (COVID-19) 是一种传染病，由一种新型和高致病性病毒株 SARS-CoV-2（严重急性呼吸道病毒综合征冠状病毒 2）。感染可能导致严重的下呼吸道感染，伴有急性呼吸窘迫和肺外感染限制 SARS-CoV-2 复制并减少感染个体器官功能障碍的治疗策略。与 COVID-19 相关的炎症将提供最大的治疗益处。多胺是天然存在的有机阳离子，对于生物体的生长和发育至关重要许多病毒需要宿主多胺才能在受感染的细胞中复制。在病毒感染期间靶向多胺代谢在体外和体内动物中显示出有希望的结果该提案的目的是测试目前 FDA 批准的两种药物依氟鸟氨酸的适用性。 (其他名称α-二氟甲基鸟氨酸或DFMO)和舒林酸，以及它们用于预防或治疗的组合 Eftornithine 是一种关键的多胺生物合成酶鸟氨酸的不可逆抑制剂。脱羧酶（ODC）是一种常见的非甾体类抗炎药（NSAID），它也会诱导。依氟鸟氨酸和舒林酸以互补的方式减少细胞内的多胺分解代谢。已确定依氟鸟氨酸/舒林酸组合的安全剂量用于预防高风险腺瘤复发（ClinicalTrials.gov 标识符 NCT00118365）。在本提案中，我们将测试以下假设：依氟鸟氨酸和舒林酸组合将减少细胞内多胺可用于冠状病毒复制以及与 COVID-19 相关的炎症。将使用细胞培养模型（具体目标 1）和 COVID-19 疾病小鼠模型来检验这一假设（具体目标 2）为依氟鸟氨酸/舒林酸组合的临床试验做准备的规划活动与 Cancer Prevention Pharmaceuticals (CPP) (www.canprevent.com) 合作的抗病毒适应症包括也包括在内。该项目的转化目标是开发预防 COVID-19 感染的有效方法以及降低 COVID-19 患者病毒感染的严重程度。预防和治疗病毒爆发的新方法。