Targeting polyamines to suppress SARS-CoV-2 related disease

摘要 2019年大流行性冠状病毒病（COVID-19）是一种传染病，由一种新的 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型）。的 感染可引起严重的下呼吸道感染，伴有急性呼吸窘迫和肺外 感染者的器官功能障碍既限制SARS-CoV-2复制又减少 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，对生长和发育都是必不可少的。 原核和真核细胞。许多病毒需要宿主多胺在感染细胞中复制， 在病毒感染过程中靶向多胺代谢在体外和体内动物中显示出有希望的结果 问题研究该提案的目的是测试两种目前FDA批准的药物依氟鸟氨酸的适用性 （另称为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 COVID-19疾病。Eftornithine是多胺生物合成关键酶鸟氨酸的不可逆抑制剂 脱羧酶（ODC）。舒林酸是一种常见的非甾体抗炎药（NSAID），也可诱导 聚胺催化剂依氟鸟氨酸和舒林酸以互补的方式起作用， 多胺水平。已经确定了依氟鸟氨酸/舒林酸组合的安全剂量，用于预防 高危腺瘤复发（ClinicalTrials.gov标识符NCT 00118365）。 在本提案中，我们将检验依氟鸟氨酸和舒林酸联合使用将减少 用于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 我将使用细胞培养模型（Specific Aim 1）和COVID-19疾病的小鼠模型来检验这一假设 （具体目标2）。计划活动，为依氟鸟氨酸/舒林酸联合治疗 与癌症预防药物（CPP）（www.canprevent.com）合作的抗病毒适应症是 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患者的病毒感染严重程度。要做到：大力发展 预防和治疗病毒爆发的新方法。

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.