Project 3: Pandemic Virus Protease Inhibitors

项目3：流行病病毒蛋白酶抑制剂

• 批准号: 10522812
• 负责人: Reuben S Harris
• 金额: $ 288万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/10522812
• 关键词: 2019-nCoV; Achievement; Active Sites; Advanced Development; Affinity; Amino Acids; Animal Model; Back; Binding; Biochemical; Biological Assay; Biological Models; Biophysics; COVID-19 pandemic; Cell model; Cells; Cellular Assay; Cessation of life; Chemicals; Chemistry; Clinical; Collaborations; Complex; Coronavirus; Cysteine; DNA; Development; Disease Outbreaks; Docking; Drug Targeting; Enzymes; Event; Flavivirus; Future; Genome; Goals; HIV-1; HIV/HCV; Hepatitis C virus; Homologous Protein; Image; Immunocompromised Host; Infection; Intervention; Knowledge; Lead; Leadership; Life Cycle Stages; Midwestern United States; Nonstructural Protein; Oral; Outcome; Papain; Pathogenesis; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Polyproteins; Positioning Attribute; Preclinical Testing; Protease Inhibitor; Proteins; RNA; Resolution; SARS-CoV-2 inhibitor; Series; Site; Structure; Surface; System; Technology; Testing; Variant; Viral; Viral Pathogenesis; Viral Physiology; Virus; Virus Diseases; Virus Replication; Work; Zika Virus; analog; antiviral drug development; base; breakthrough infection; chemical synthesis; design; drug development; gain of function; high throughput screening; in vivo; in vivo Model; industry partner; inhibitor; innovation; multidisciplinary; novel; pandemic disease; prevent; research clinical testing; resistance mechanism; scale up; screening; small molecule; small molecule inhibitor; stem; success; vaccination strategy; virology; virtual screening; zoonotic coronavirus

Project 3 – Pandemic Virus Protease Inhibitors ABSTRACT Viral proteases are high-priority drug targets due to their essential functions in virus replication and also unambiguous evidence for druggability, with HIV and HCV drugs as major success stories. This project is organized with the goal of developing novel chemical inhibitors of coronavirus and flavivirus proteases. Specifically, SARS-CoV-2 has two proteases, Papain-Like Protease (PLPro) and Main Protease (MPro), that catalyze 3 and 11 viral polyprotein cleavage events, respectively. SARS-CoV-2 MPro is an attractive drug target due to the large number of essential cleavages at the earliest stages of viral infection and the fact that it has multiple druggable surfaces, including an active site cysteine amenable to covalent adduction. It also shares mechanistic and structural features with related coronavirus MPro proteins, which suggests that it may be possible to develop a pan-coronavirus MPro inhibitor for use against the current pandemic virus and for future use against future coronavirus zoonotic events. Similarly, flaviviruses such as Zika virus require protease function for the earliest viral life cycle stages. The Zika virus NS2B-NS3 protease also has multiple druggable surfaces, and amino acid and structural similarities with related flavivirus proteases suggest potential for broader spectrum inhibition. As preliminary studies, we have designed and optimized multiple assays for these viral proteases, contributed to the wealth of structural, biophysical, and computational knowledge of these drug targets, and already obtained multiple series of candidate small molecule inhibitors. We propose two specific aims in order to expedite the achievement of our central goal. In Aim 1, we will leverage our assays and work closely with our screening (Core B) and structural/computational/virology cores (Cores D-E) to identify additional small molecule inhibitors of these two enzymes in order to maximize chances of obtaining hit series for further development. In Aim 2, candidate hits will be prioritized for further development by testing in orthologous secondary and tertiary assays and, in close collaboration with our chemistry/DMPK and structural/computational cores (Cores C-D), elaborated by systematically designing and testing related commercial and novel synthesized molecules. At all stages of development, representative hits from each series will be evaluated quantitatively using cellular assays and, in close collaboration with our virology core (Core E), also tested rigorously using the best available systems for virus replication and pathogenesis in vivo. The major deliverable from this highly integrated and collaborative effort will be multiple novel lead inhibitors for pre-clinical and clinical testing with industry partners with the hope of soon-fortifying the arsenal of drugs that will be required to end the COVID-19 pandemic and help neutralize future outbreaks.

项目 3 – 大流行病毒蛋白酶抑制剂 抽象的 病毒蛋白酶是高度优先的药物靶点，因为它们在病毒复制中具有重要功能，而且 明确的成药性证据，艾滋病毒和丙肝病毒药物是主要的成功案例。这个项目是 该组织的目标是开发冠状病毒和黄病毒蛋白酶的新型化学抑制剂。 具体来说，SARS-CoV-2 有两种蛋白酶，木瓜蛋白酶样蛋白酶 (PLPro) 和主蛋白酶 (MPro)， 分别催化 3 次和 11 次病毒多蛋白裂解事件。 SARS-CoV-2 MPro 是一个有吸引力的药物靶点 由于在病毒感染的最早阶段存在大量的必需裂解，并且它具有 多个可成药表面，包括易于共价加合的活性位点半胱氨酸。它还分享 相关冠状病毒 MPro 蛋白的机制和结构特征，这表明这可能是可能的 开发一种泛冠状病毒 MPro 抑制剂，用于对抗当前的大流行病毒，并用于未来对抗 未来的冠状病毒人畜共患事件。同样，寨卡病毒等黄病毒也需要蛋白酶功能 最早的病毒生命周期阶段。寨卡病毒 NS2B-NS3 蛋白酶还具有多个可成药表面，并且 与相关黄病毒蛋白酶的氨基酸和结构相似性表明具有更广谱的潜力 抑制。作为初步研究，我们为这些病毒蛋白酶设计并优化了多种检测方法， 贡献了这些药物靶标的丰富的结构、生物物理和计算知识，并且 已获得多个系列的候选小分子抑制剂。我们提出两个具体目标 加快实现我们的中心目标。在目标 1 中，我们将利用我们的检测方法并与我们的密切合作 筛选（核心 B）和结构/计算/病毒学核心（核心 D-E）以识别其他小分子 这两种酶的抑制剂，以便最大限度地提高获得热门系列产品以供进一步开发的机会。在 目标 2，候选命中将优先通过在直系同源二级和三级测试中进行进一步开发 分析，并与我们的化学/DMPK 和结构/计算核心（核心 C-D）密切合作， 通过系统地设计和测试相关的商业和新型合成分子来阐述。根本 在开发阶段，每个系列的代表性命中将使用细胞测定进行定量评估 并且与我们的病毒学核心（核心 E）密切合作，还使用最佳可用系统进行了严格测试 用于病毒在体内的复制和发病机制。这种高度集成和协作的主要成果 将与行业合作伙伴一起努力将多种新型先导抑制剂用于临床前和临床测试 尽快加强结束 COVID-19 大流行并帮助消除病毒所需的药物库 未来的爆发。