VPS34 inhibitors as SARS-CoV-2 antivirals

VPS34 抑制剂作为 SARS-CoV-2 抗病毒药物

• 批准号: 10534720
• 负责人: Christopher F Basler
• 金额: $ 41.59万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534720
• 关键词: VPS34; inhibitors; SARS; CoV; antivirals

Summary SARS-CoV-2, a Betacoronavirus genus, is an enveloped positive-sense, RNA virus responsible for a current pandemic. Because of its profound impact on society and human health there is an urgent need to understand SARS-CoV-2 replication requirements and to identify therapeutic strategies. Repurposing drugs developed for other purposes may provide a shortcut to therapeutic development. The use of compounds known to target specific host factors may also elucidate key pathways needed for virus replication. Coronavirus (CoV) replication involves multiple critical interactions with host cell membranes. One of the most striking features of CoV infection is the establishment of membrane-associated replication organelles that serve as the main sites of viral RNA synthesis. The origin of these membrane organelles is incompletely understood. Because the specific host pathways required for SARS-CoV-2 replication organelle formation are not defined, we asked whether SARS-CoV-2 is susceptible to modulators of lipid metabolism by assessing the sensitivity of the virus to VPS34 inhibitors of VPS34, a lipid kinase required for autophagy and endosomal trafficking; Triacsin C, an inhibitor of long chain fatty acyl CoA synthetase (ACSL) and Orlistat, an inhibitor of fatty acid synthase (FASN). Our preliminary data indicate that inhibitors of VPS34 potently inhibited SARS-CoV-2 replication, whereas an FDA- approved inhibitor of a different class of PI3K had minimal effect on replication. Targeting FASN and ACSL also impairs SARS-CoV-2 replication. These data suggest that VPS34, ACSL and FASN play important roles in replication center formation and virus growth and suggest these enzymes as therapeutic targets. We will test the hypothesis that VPS34, ACSL and FASN are critical for SARS-Cov-2 infection by evaluating additional small molecule inhibitors of these enzymes and by measuring SARS-CoV-2 replication in genetic knockdowns or knockouts of these host enzymes. We will define mechanisms of inhibition and test the hypothesis that generation of membrane-associated viral replication centers will be disrupted. Finally, we will assess the in vivo efficacy of VSP34 inhibitor PIK-III and systemically administered Orlistat in SARS-coV-2- infected hamsters to evaluate the therapeutic potential of inhibitors of lipid metabolism.

概括 SARS-COV-2是一种betacoronavirus属，是一种包膜的阳性，RNA病毒负责 对于当前的大流行。由于它对社会和人类健康的深远影响 迫切需要了解SARS-COV-2复制要求并确定治疗 策略。为其他目的开发的重新利用药物可能会为治疗提供快捷方式 发展。用于针对特定宿主因子的已知化合物的使用也可能阐明键 病毒复制所需的途径。冠状病毒（COV）复制涉及多个关键 与宿主细胞膜的相互作用。 COV感染最引人注目的特征之一是 建立与膜相关的复制细胞器，作为病毒的主要部位 RNA合成。这些膜细胞器的起源尚不完全理解。因为 SARS-COV-2复制细胞器形成所需的特定主机途径不是 定义，我们询问SARS-COV-2是否容易受到脂质代谢调节剂的影响 评估病毒对VPS34 VPS34抑制剂的敏感性，VPS34是一种脂质激酶 自噬和内体贩运； Triacsin C，长链脂肪酰基COA的抑制剂 合成酶（ACSL）和Orlistat，脂肪酸合酶（FASN）的抑制剂。我们的初步数据 表明VPS34的抑制剂有效抑制SARS-COV-2复制，而FDA- 批准的不同类别PI3K的抑制剂对复制的影响很小。定位FASN ACSL还会损害SARS-COV-2复制。这些数据表明VPS34，ACSL和 FASN在复制中心形成和病毒生长中起重要作用，并提出这些作用 酶作为治疗靶标。我们将测试VPS34，ACSL和FASN的假设 通过评估这些其他小分子抑制剂，对SARS-COV-2感染至关重要 酶并通过测量遗传敲低或敲除中的SARS-COV-2复制 宿主酶。我们将定义抑制机制，并检验产生的假设 膜相关的病毒复制中心将被破坏。最后，我们将评估 VSP34抑制剂PIK-III和在SARS-COV-2-中的orlistat的体内功效 感染的仓鼠以评估脂质代谢抑制剂的治疗潜力。