Targeting polyamines to suppress SARS-CoV-2 related disease

摘要 2019年大流行冠状病毒病(新冠肺炎)是一种传染病，由一种新型的和 高致病性病毒株SARS-CoV-2(严重急性呼吸道综合征冠状病毒2)。这个 感染可引起严重下呼吸道感染，并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复制又减少的治疗策略 与新冠肺炎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，对两者的生长和发育都是必不可少的。 原核细胞和真核细胞。许多病毒需要宿主多胺在受感染的细胞中复制，并 病毒感染期间靶向多胺代谢在体外和体内动物实验中显示出良好的结果 学习。这项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 (又名α-二氟甲基鸟氨酸或DFMO)和舒林酸及其预防或治疗的组合 新冠肺炎病的发病率。Eftornithine是关键的多胺生物合成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类固醇抗炎药，它还会导致 多胺分解代谢。依氟鸟氨酸和舒林酸以互补的方式发挥作用，减少细胞内 多胺水平。已经确定了依氟鸟氨酸/舒林酸联合用药的安全剂量，以预防 高危腺瘤的复发(ClinicalTrials.gov标识NCT00118365)。 在这项建议中，我们将检验依氟鸟氨酸和舒林酸联合使用将降低 细胞内多胺可用于冠状病毒复制，以及与新冠肺炎相关的炎症。我们 将使用细胞培养模型(特定目标1)和新冠肺炎病的小鼠模型来验证这一假设 (具体目标2)。规划依氟鸟氨酸/舒林酸联合用药的临床试验活动 与癌症预防药物(CPP)(www.canprevenent.com)合作的抗病毒适应症有 也包括在内。 该项目的翻译目标是开发预防新冠肺炎感染的有效方法 以及降低新冠肺炎患者的病毒感染严重程度。发展是必不可少的。 预防和治疗病毒暴发的新方法。

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.