Development of an Oral Pan-Coronavirus Drug Cocktail

口服泛冠状病毒药物混合物的开发

• 批准号: 10714472
• 负责人: STEPHEN J. POLYAK
• 金额: $ 70.24万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714472
• 关键词: 2019-nCoV; Achievement; Antibodies; Antiviral Agents; Authorization documentation; Belgium; COVID-19 pandemic; COVID-19 therapeutics; Cell Line; Cells; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Coronavirus; Coronavirus Infections; Data; Development; Disease Outbreaks; Dose; Drug Combinations; Drug Interactions; Drug Kinetics; Drug resistance; Effectiveness; Enzymes; Evolution; Experimental Designs; Failure; Family; Future; General Population; Goals; Hamsters; Hospitalization; Human; Immunocompromised Host; In Vitro; Incidence; Infection; Lead; Long COVID; Lower respiratory tract structure; Lung; Measures; Medicine; Middle East Respiratory Syndrome; Modeling; Monoclonal Antibodies; Mus; Oral; Patients; Paxlovid; Persons; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Property; Prophylactic treatment; Protease Inhibitor; Readiness; Regimen; Research; Resistance; Resistance development; Rodent; Rodent Model; SARS-CoV-2 B.1.1.529; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; SCID Mice; Scientist; Self Administration; Severe Acute Respiratory Syndrome; Severities; Source; Symptoms; Testing; Therapeutic; Time; Tissues; Upper respiratory tract; Vaccines; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; Virus Shedding; Work; antiviral drug development; authority; base; cost; design; dosage; drug efficacy; efficacy testing; experimental study; future outbreak; future pandemic; global health; hospitalization rates; immunodeficient mouse model; improved; in vivo; in vivo evaluation; mathematical methods; mathematical model; molnupiravir; mutant; new epidemic; nirmatrelvir; novel; novel coronavirus; pandemic coronavirus; pandemic disease; pandemic preparedness; pandemic response; pharmacodynamic model; pharmacokinetic model; prophylactic; remdesivir; resistance mutation; response; small molecule; success; synergism; therapy duration; trial design; variants of concern; viral outbreak; viral rebound; virus development; virus identification

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.

抽象的 该 R01 由美国和比利时科学家之间的合作组成，旨在开发协同效应 与 SARS-CoV-2/COVID-19 大流行的演变保持同步的抗病毒药物组合，以及 相关冠状病毒的未来爆发。我们将利用 i) 协同活动的原理 药物组合和 ii) 优化人体剂量的新颖数学方法，用于治疗新兴和 重新出现的具有大流行潜力的冠状病毒。我们将确定 i) 靶向的药物组合 支持病毒感染的保守细胞因子，和/或 ii) 针对病毒所必需的病毒酶 复制，开发针对多种冠状病毒的新型抗病毒药物组合（即泛家族药物 鸡尾酒）。根据我们之前的工作，数学建模方法将用于 i) 识别药物 具有协同抗病毒作用的组合，ii) 优先考虑药物组合和剂量策略以进行测试 病毒感染和疾病的啮齿动物模型，以及 iii) 预测不同剂量的人体体内功效 策略。我们的研究计划为全球大流行应对和准备提供了积极主动的方法， 交付物由 i) 化合物组合组成，这些化合物可有效、协同抑制 多种冠状病毒，并且具有足够高且持久的血浆和组织浓度，并且 ii) 公开 可用的协调临床试验设计，将允许在同一时间并行有效地测试多种药物 新流行病的开始。由于该方法适用于任何病毒家族，该项目预示着全球 改善对普通民众的保护，使其免受现有病毒威胁，加强防备，从而产生影响 和应对未来病毒爆发，并提供可立即测试和部署的口服药物 填补病毒识别、病毒开发和部署之间时间空白的组合 序列特异性疫苗、抗体和药物。

项目成果

Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents.

药物组合的双向药效学模型及其在重新利用的埃博拉和 SARS-CoV-2 药物对中的应用。

• 发表时间: 2024-04-03
• 影响因子: 4.9
• 作者: Xu, Shuang;Esmaeili, Shadisadat;Cardozo;Goyal, Ashish;White, Judith M;Polyak, Stephen J;Schiffer, Joshua T
• 通讯作者: Schiffer, Joshua T