Development of an Oral Pan-Coronavirus Drug Cocktail

摘要 该R 01包括美国和比利时科学家之间的合作，旨在开发协同 与SARS-CoV-2/COVID-19大流行的演变保持同步的抗病毒药物组合， 相关冠状病毒的未来爆发。我们将利用i）协同活动的原则， 药物组合和ii）新的数学方法，以优化用于治疗新出现的和 重新出现的具有大流行潜力的冠状病毒。我们将确定药物组合，i）靶向 支持病毒感染的保守细胞因子，和/或ii）靶向病毒感染所必需的病毒酶， 复制，以开发针对多种冠状病毒的新型抗病毒药物组合（即，泛家庭用药 鸡尾酒）。基于我们以前的工作，数学建模方法将用于i）识别药物 具有协同抗病毒作用的药物组合，ii）优先考虑药物组合和给药策略， 病毒感染和疾病的啮齿动物模型，和iii）预测在人体内用各种剂量的 战略布局我们的研究计划为全球流行病的应对和准备提供了一种积极主动的方法， i）化合物的组合，所述化合物赋予有效的协同抑制， 多种冠状病毒，并具有足够高和持久的血浆和组织浓度，以及ii）公众 现有的协调一致的临床试验设计，将允许有效的测试多种药物在平行 新的流行病的开始。由于该方法适用于任何病毒家族，该项目预示着全球 通过加强对普通民众的保护，使其免受现有病毒威胁的影响， 以及对未来病毒爆发的反应，并提供可立即测试和部署的口服药物 这些组合填补了病毒识别与病毒的开发和部署之间的时间空白， 序列特异性疫苗、抗体和药物。

ABSTRACT This R01 comprises a collaboration between scientists in the US and Belgium that seeks to develop synergistic antiviral drug combinations that keep pace with the evolution of the SARS-CoV-2/COVID-19 pandemic and future outbreaks of related coronaviruses. We will exploit i) the principles of synergistic activity that arise with drug combinations and ii) novel mathematical approaches to optimize human dosing for treating emerging and re-emerging coronaviruses with pandemic potential. We will identify combinations of drugs that i) target conserved cellular factors that support virus infection, and/or ii) target viral enzymes that are essential for viral replication, to develop novel antiviral drug combinations against multiple coronaviruses (i.e., a pan-family drug cocktail). Based on our previous work, mathematical modeling approaches will be used to i) identify drug combinations with synergistic antiviral action, ii) prioritize drug combinations and dosing strategies for testing in rodent models of virus infection and disease, and iii) predict in vivo efficacy in humans with various dosing strategies. Our research plan provides a proactive approach for global pandemic response and preparedness, with deliverables consisting of i) combinations of compounds that confer potent, synergistic suppression of multiple coronaviruses and have sufficiently high and durable plasma and tissue concentrations and ii) publicly available harmonized clinical trial designs that will allow for efficient testing of multiple agents in parallel at the inception of new epidemics. As the approach is applicable to any virus family, the project portends global impact by improving protection of the general population against existing viral threats, enhancing preparedness and response for future viral outbreaks, and offering immediately testable and deployable oral drug combinations that fill the time void between virus identification and development and deployment of viral sequence-specific vaccines, antibodies, and drugs.