Targeting druggable coronavirus proteins

靶向可药物化的冠状病毒蛋白

• 批准号: 10514326
• 负责人: Michael R. Farzan
• 金额: $ 578.68万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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/10514326
• 关键词: 2019-nCoV; Address; Back; Binding; Biology; COVID-19 treatment; Cells; Cellular Membrane; Chemicals; Chemistry; Complement; Complex; Coronavirus; Custom; DNA; DNA-Directed RNA Polymerase; Development; Drug Targeting; E protein; Florida; Fluorescence; Genome; Goals; Inhalation; Investigational Drugs; Ion Channel; Ion Channel Protein; Laboratories; Lead; Mediating; Medicine; Membrane; Membrane Fusion; Molecular; Nucleocapsid; Nucleocapsid Proteins; Peptide Hydrolases; Process; Property; Prophylactic treatment; Proteins; Public Health; RNA; Replication-Associated Process; Research; Resources; Role; Running; SARS coronavirus; SARS-CoV-2 entry inhibitor; SARS-CoV-2 inhibitor; SH2D3A gene; Sarbecovirus; Series; Structure; Toxic effect; Validation; Viral; Virion; Virus; analog; base; cellular targeting; cross reactivity; design; druggable target; ds-DNA; helicase; high risk; high throughput screening; in silico; in vivo; inhibitor; lead optimization; novel; pandemic preparedness; replicase; success; validation studies; viral RNA

SUMMARY Coronaviruses, including SARS-CoV-2, pose obvious and imminent dangers to public health. This CAMPP proposal develops compounds that target multiple coronaviruses proteins and replication processes. These proteins include well established drug targets such as protease (Project 1) and replicase (Project 2), and as well as higher risk targets (Project 4). Project 3 – Targeting Druggable Coronavirus Proteins focuses on four less established viral processes that nonetheless have been successfully targeted in at least one proof-of-principle example. These include the coronaviral helicase nsp13 (Aim 1, led by Sumit Chandra at Scripps Research), the nucleocapsid (N) protein, which packages the RNA genome and associates with the budding virion (Aim 2, led by Suganya Selvarajah at Prosetta), the E protein, which encodes an ion channel whose activity likely contributes to virion assembly (Aim 3, led by John Guatelli from UCSD), and the spike (S) protein with mediates fusion of the viral and cellular membranes (Aim 4, lead by Michael Farzan at Scripps Florida). These four targets afford four parallel “shots on goal”. In each case, the lead laboratory has identified novel proof-of-principle chemical matter inhibiting the activity of each protein. These compounds are developed through a common pipeline, and in parallel each aim pursues a custom high-throughput screen designed to address the challenges unique to each target. In the later years of the proposal developmental resources are allocated to the most promising compounds. The overall structure of this proposal is thus designed to maximize the chance of developing an effective inhibitor or coronavirus replication.

总结 包括SARS-CoV-2在内的冠状病毒对公共卫生构成明显和紧迫的威胁。这 CAMPP提案开发针对多种冠状病毒蛋白和复制的化合物 流程.这些蛋白质包括已确立的药物靶标，如蛋白酶（项目1）和 复制酶（项目2），以及高风险目标（项目4）。项目3 -靶向药物 Coronavirus Proteins专注于四种不太成熟的病毒过程，尽管如此， 在至少一个原理证明示例中成功地针对。其中包括冠状病毒解旋酶 nsp 13（Aim 1，由Scripps Research的Sumit Chandra领导），核衣壳（N）蛋白， RNA基因组并与萌芽病毒粒子相关（Aim 2，由Prosetta的Suganya Selvarajah领导）， E蛋白编码离子通道，其活性可能有助于病毒体组装（Aim 3， 由加州大学圣地亚哥分校的John Guatelli领导），以及介导病毒和细胞融合的刺突（S）蛋白。 膜（Aim 4，由佛罗里达斯克里普斯的Michael Farzan领导）。这四个目标提供了四个平行的 “射门得分”在每一种情况下，领先的实验室都确定了新的原理证明化学物质 抑制每种蛋白质的活性。这些化合物通过共同的管道开发， 同时，每个目标都追求定制的高通量筛选，旨在解决独特的挑战， 每个目标。在提案的后几年，发展资源分配给最需要的人， 有前途的化合物。因此，本提案的总体结构旨在最大限度地提高 开发有效的抑制剂或冠状病毒复制。