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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：
10320073
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320073
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 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 mouse model neutrophil novel novel strategies pathogenic virus protein expression receptor expression 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.

摘要