Center for Antiviral Medicines & Pandemic Preparedness (CAMPP)

抗病毒药物中心

基本信息

批准号：
10514317
负责人：
SUMIT K CHANDA
金额：
$ 6762.42万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10514317
关键词：
2019-nCoV Animal Model Antibody Therapy Antiviral Agents Antiviral Therapy Architecture Back Biological Availability Biological Products COVID-19 pandemic COVID-19 therapeutics COVID-19 treatment Capsid Chemicals Chemistry Clinical Clinical Trials Computational Biology Coronavirus Dengue Virus Development Disease Outbreaks Dose Drug Targeting Ebola Ebola virus Ensure Equilibrium FDA Emergency Use Authorization Filovirus Flavivirus Foundations Funding Future Genetic Transcription Goals Grant Health Human Human Resources Individual Industry Infection Infrastructure Intention Interdisciplinary Study Ion Channel Lassa virus Mediating Medicine Middle East Respiratory Syndrome Monoclonal Antibodies Nucleocapsid Nucleosides Oral Organoids Orthobunyavirus Outcome Peptide Hydrolases Pharmaceutical Preparations Pharmacologic Substance Pharmacology Polymerase Positioning Attribute Process Protease Inhibitor Proteins RNA RNA Polymerase Inhibitor RNA Synthesis Inhibitors RNA Viruses RNA chemical synthesis Readiness Research Institute Research Personnel Ritonavir SARS-CoV-2 infection SARS-CoV-2 inhibitor Severe Acute Respiratory Syndrome Severe Fever with Thrombocytopenia Syndrome Virus Structural Protein Structure Technology Testing Therapeutic Viral Viral Proteins Virus Virus Diseases West Nile virus Work ZIKA antiviral drug development base biopharmaceutical industry chemoproteomics clinical development drug candidate drug development drug discovery flexibility helicase hemorrhagic fever virus high risk human disease in vivo inhibitor innovation interdisciplinary approach lead optimization molnupiravir mortality multidisciplinary next generation novel novel strategies nucleoside inhibitor pandemic disease pandemic preparedness pre-clinical preclinical study programs remdesivir research clinical testing screening small molecule libraries structural biology success treatment center virology

项目摘要

SUMMARY The ongoing COVID-19 pandemic has brought to light an urgent need to enhance the therapeutic preparedness for future viral outbreaks and pandemics. The overarching goal of the “Center for Antiviral Medicines & Pandemic Preparedness” (CAMPP) is thus to develop novel strategies and enhance the drug discovery pipelines for direct-acting antivirals against RNA viruses of pandemic concern. The specific focus of CAMPP will be to develop antivirals against coronaviruses SARS-CoV-2 (SCV2), SARS and MERS; flaviviruses including Zika, West Nile and Dengue virus; and hemorrhagic fever viruses including the filovirus Ebola, and bunyaviruses Severe fever with thrombocytopenia syndrome virus and Lassa virus. Infection by any of these agents has the potential to cause severe human disease with significant mortality rates and current options for antiviral treatments are limited. The antiviral drug remdesivir and several monoclonal antibody treatments have received emergency use authorization (EUA) for treatment of COVID-19, and the polymerase inhibitor molnupiravir by Merck is expected to be granted EUA in the near future. Monoclonal antibodies are also available to treat Ebola virus infection, however, none of these drugs can be administered orally, posing additional challenges in treating early infection. There are no approved treatments for the CAMPP flaviviruses and hemorrhagic fever viruses. Toward this end, we have assembled a world class multidisciplinary team of investigators with expertise in virology of relevant viruses, structural and computational biology, chemoproteomics, pharmacology and organoid/animal models, who will work closely with the drug development experts at the drug discovery division of The Scripps Research Institute, Calibr, to further the development of four major classes of promising assets in our drug discovery pipeline. First, we propose to develop a potentially best-in-class, orally bioavailable coronavirus protease (CLpro) inhibitor for coronaviruses including SCV2, from a late-stage drug asset undergoing ADME optimization that is expected to enter IND-enabling studies within the next three years. Second, we will identify and optimize RNA polymerase inhibitors for SCV2 and other CAMPP viruses, with the goal of reaching IND-enabling studies within the next four years. The third focus of our proposal is to develop antivirals against other ‘druggable’ proteins encoded by SCV2 and additional viruses posing a pandemic threat; these assets include inhibitors of SCV2 helicase, E-protein encoded ion channel activity, entry and fusion activities, and nucleocapsid, with the goal of obtaining in vivo proof-of-concept for a subset of these mid-stage assets. Finally, we propose to target traditionally considered ‘undruggable’ non-enzymatic proteins including SCV2 and flaviviral structural proteins as well as RNA structure, to develop novel strategies for antiviral drug development. CAMPP provides a highly integrated infrastructure of investigators, expertise and external pharmaceutical and founding partners that will ensure the Center’s success in achieving our goals and navigating challenges of the drug discovery process.

概括持续的 COVID-19 大流行凸显了加强治疗准备的迫切需要 “抗病毒药物与治疗中心”的总体目标。因此，“流行病防范”（CAMPP）旨在制定新策略并加强药物发现 CAMPP 的具体重点将是针对大流行病的 RNA 病毒的直接作用抗病毒药物的管道。开发针对冠状病毒 SARS-CoV-2 (SCV2)、SARS 和 MERS 的抗病毒药物，包括黄病毒；寨卡病毒、西尼罗河病毒和登革热病毒；以及出血热病毒，包括丝状病毒、埃博拉病毒和布尼亚病毒血小板减少综合征病毒和拉沙病毒感染引起的严重发烧。可能导致严重的人类疾病，死亡率很高，以及当前的抗病毒选择抗病毒药物瑞德西韦和几种单克隆治疗抗体的治疗效果有限。用于治疗 COVID-19 的紧急使用授权 (EUA)，以及聚合酶抑制剂 molnupiravir 默克预计将在不久的将来获得 EUA，单克隆抗体也可用于治疗埃博拉病毒。然而，这些药物都不能口服治疗病毒感染，这给治疗带来了额外的挑战早期感染尚无针对 CAMPP 黄病毒和出血热病毒的批准治疗方法。为此，我们组建了一支世界一流的多学科研究团队，他们拥有以下方面的专业知识：相关病毒的病毒学、结构和计算生物学、化学蛋白质组学、药理学和类器官/动物模型，他们将与药物发现部门的药物开发专家密切合作斯克里普斯研究所 (Scripps Research Institute) 的 Calibr 旨在进一步开发四大类有前途的资产首先，我们建议开发一种潜在的同类最佳口服生物可利用药物。用于包括 SCV2 在内的冠状病毒的冠状病毒蛋白酶 (CLpro) 抑制剂，来自一项正在进行的后期药物资产 ADME 优化预计将在未来三年内进入 IND 支持研究第二，我们将。识别并优化 SCV2 和其他 CAMPP 病毒的 RNA 聚合酶抑制剂，目标是我们提案的第三个重点是开发抗病毒药物。 SCV2 编码的其他“可成药”蛋白质和其他对这些资产构成大流行威胁的病毒；包括 SCV2 解旋酶抑制剂、E 蛋白编码离子通道活性、进入和融合活性，以及核衣壳，目的是获得这些中期资产子集的体内概念验证。我们建议针对传统上认为“不可成药”的非酶蛋白，包括 SCV2 和黄病毒结构蛋白以及 RNA 结构，以开发抗病毒药物开发的新策略。提供由研究者、专业知识和外部制药及创始机构组成的高度集成的基础设施将确保中心成功实现我们的目标并应对药物挑战的合作伙伴发现过程。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SARS-CoV-2 3CL-protease inhibitors derived from ML300: investigation of P1 and replacements of the 1,2,3-benzotriazole.

源自 ML300 的 SARS-CoV-2 3CL 蛋白酶抑制剂：P1 的研究和 1,2,3-苯并三唑的替代品。

DOI：
10.21203/rs.3.rs-2880312/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Hooper,Alice;Macdonald,JonathanD;Reilly,Brenna;Maw,Joshua;Wirrick,AidanP;Han,SangHoon;Lindsey,AAbigail;Rico,EmmaG;Romigh,Todd;Goins,ChristopherM;Wang,NancyS;Stauffer,Shaun
通讯作者：
Stauffer,Shaun