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：
10202992
负责人：
DAVID G BESSELSEN
金额：
$ 30.7万
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 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10202992
关键词：
2019-nCoV ACE2 Adult Respiratory Distress Syndrome Affect Angiotensin Receptor Animal Model Animals Antiviral Agents 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 Lead Life Cycle Stages Lower Respiratory Tract Infection 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 Pharmacology 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 Proteins Virus Virus Diseases Virus Replication Work adenoma anti-viral efficacy base cancer prevention carcinogenesis cellular targeting colon cancer prevention cytokine disorder later incidence prevention disorder prevention drug development efficacy testing endoplasmic reticulum stress extracellular gastrointestinal system high risk in vivo inhibitor/antagonist mouse model neutrophil novel novel strategies pathogenic virus protein expression receptor expression respiratory response stool sample 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 2019年大流行冠状病毒疾病（Covid-19）是一种传染病，是由新颖和高致病性病毒菌株SARS-COV-2（严重的急性呼吸道病毒综合征冠状病毒2）。这感染可能导致严重的下呼吸道感染，急性呼吸窘迫和肺外感染受感染个体的器官失调。两者都限制SARS-COV-2复制并减少的治疗策略与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，这对于两者的生长和发展至关重要原核细胞和真核细胞。许多病毒需要宿主多胺在感染细胞中复制，并且在病毒感染期间靶向多胺代谢显示出有望在体外和体内动物研究。该建议的目的是测试两种目前FDA批准的药物Eflornithine的适用性（其他名称α-二氟甲基氨酸或DFMO）和Sulindac，以及它们用于预防或治疗的组合 Covid-19疾病。 eftornithine是一种不可逆的多胺生物合成酶鸟氨酸的不可逆抑制剂脱羧酶（ODC）。 Sulindac是一种常见的非甾体类抗炎药（NSAIDS），它也诱导多胺分解代谢。 Eflornithine和Sulindac以完整的方式减少细胞内多胺水平。已经建立了eflornithine/sulindac组合的安全剂量以预防高风险腺瘤的复发（ClinicalTrials.gov标识符NCT00118365）。在此提案中，我们将检验以下假设：eflornithine和sulindac组合将减少冠状病毒复制的细胞内多胺可用性，以及与Covid-19相关的炎症。我们将使用细胞培养模型（特定目标1）和COVID-19疾病的小鼠模型检验该假设（特定目标2）。计划活动，准备临床试验的eflornithine/sulindac组合与癌症预防药物合作（CPP）（www.canprevent.com）合作的抗病毒指示为还包括。该项目的翻译目标是开发预防预防的有效方法以及在199例患者中降低病毒感染的严重程度。发展至关重要预防和治疗病毒爆发的新方法。