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.

概括 包括 SARS-CoV-2 在内的冠状病毒对公众健康构成明显且迫在眉睫的危险。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。这些蛋白质包括成熟的药物靶点，例如蛋白酶（项目 1）和 复制酶（项目 2），以及更高风险的目标（项目 4）。项目 3 – 针对可成药的目标 冠状病毒蛋白重点关注四种不太成熟的病毒过程，但这些过程已被证实 至少在一个原理验证示例中成功定位。其中包括冠状病毒解旋酶 nsp13（目标 1，由 Scripps Research 的 Sumit Chandra 领导），核衣壳 (N) 蛋白，它包装 RNA 基因组并与出芽的病毒颗粒相关联（目标 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粒子组装（目标 3， 由来自 UCSD 的 John Guatelli 领导），刺突 (S) 蛋白介导病毒和细胞的融合 膜（目标 4，由佛罗里达州斯克里普斯的 Michael Farzan 领导）。这四个目标提供了四个并行的 “射门”。在每种情况下，牵头实验室都已鉴定出新颖的原理验证化学物质 抑制每种蛋白质的活性。这些化合物是通过共同的管道开发的，并且 同时，每个目标都追求定制的高通量屏幕，旨在应对独特的挑战 到每个目标。在该提案的最后几年，发展资源被分配给最 有前途的化合物。因此，该提案的总体结构旨在最大限度地提高 开发有效的冠状病毒复制抑制剂。