EVOLVING VIRUS-SPECIFIC sACE2 MIMICS FOR COMPETITIVE INHIBITION OF SARS-CoV-2

进化病毒特异性 sACE2 模拟物以竞争性抑制 SARS-CoV-2

• 批准号: 10175307
• 负责人: Kevin Esvelt
• 金额: $ 39.93万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10175307
• 关键词: 2019-nCoV; Affect; Affinity; Albumins; Antiviral Agents; Binding; Binding Proteins; Biological; Biological Assay; COVID-19 pandemic; Cells; Clinical; Clinical Trials; Communicable Diseases; Data; Directed Molecular Evolution; Disease Outbreaks; Dose; Effectiveness; Engineering; Evolution; Exhibits; Future; Generations; Goals; Human; Human body; Integrin Binding; Integrins; Laboratories; Left; Libraries; Machine Learning; Medicine; Mus; Mutation; Pathogenicity; Patients; Process; Proteins; Recombinants; Safety; Signal Transduction; Therapeutic; Time; Toxic effect; Training; Variant; Viral; Virus; Virus Diseases; Virus Inhibitors; base; combat; cross reactivity; deep learning; design; global health emergency; immunogenicity; improved; in vivo; inhibitor/antagonist; lead candidate; mutant; novel; novel therapeutics; prevent; receptor; side effect

PROJECT SUMMARY The rapid spread of the highly-pathogenic, novel SARS-coronavirus 2 (SARS-CoV-2) has caused a global health emergency. Thus, there is a desperate need for effective antiviral therapeutics to counteract this virus. The SARS-CoV-2 virus enters cells using the ACE2 receptor1 which binds the viral spike protein2. In its soluble form, ACE2 (sACE2) has the potential to be used as a stable and non-immunogenic competitive inhibitor to SARS-CoV-2 and is presently being explored in clinical trials3. Due to the potential negative side effects of anti-spike mAbs18, and the fact that ACE2 exhibits other biological roles4–6 including integrin signaling regulation7,8, spike-specific receptor mimics would yield novel therapeutics for SARS-CoV-2 and potentially other highly infectious diseases. This proposal seeks to use machine learning and directed evolution to develop high affinity, yet endogenously-inactive mimics of sACE2 in order to create rapidly implementable therapeutics to combat SARS-CoV-2 and potential corona-like viruses. This approach would allow for the generation of scalable and translatable biologics, and provide a platform to rapidly course-correct for potential mutations that may arise in the future. Utilizing deep-learning with UniRep49, will design and generate sACE2 variants that tightly bind the SARS-CoV2-2 spike protein but do not cross-interact with endogenous targets such as integrins [Aim 1]. Simultaneously, we will perform directed evolution to optimize spike-binding and select against variants that bind endogenous proteins [Aim 2]. Finally, we will identify lead candidates and evaluate the tolerance and immunogenicity of engineered sACE2 variants in mice [Aim 3]. Collectively, this proposal will develop highly-specific ACE2 receptor mimics in order to create novel antivirals with minimal immunogenicity in time to save lives and prevent future outbreaks. 10

项目概要 高致病性新型 SARS 冠状病毒 2 (SARS-CoV-2) 的迅速传播已引起全球范围内的恐慌。 卫生紧急情况。因此，迫切需要有效的抗病毒疗法来对抗这种病毒。 SARS-CoV-2 病毒使用 ACE2 受体 1 进入细胞，该受体 1 与病毒刺突蛋白 2 结合。在其 可溶形式的 ACE2 (sACE2) 有潜力用作稳定且非免疫原性的竞争性药物 SARS-CoV-2 抑制剂，目前正在临床试验中进行探索3。由于潜在的负面影响 抗刺突 mAbs18 的作用，以及 ACE2 表现出其他生物学作用4-6（包括整合素）的事实 信号调节7,8，刺突特异性受体模拟物将产生针对 SARS-CoV-2 和 潜在的其他高度传染性疾病。 该提案旨在利用机器学习和定向进化来发展高亲和力，但 sACE2 的内源性失活模拟物，以创建快速可实施的治疗方法来对抗 SARS-CoV-2 和潜在的冠状病毒。这种方法将允许生成可扩展且 可翻译的生物制剂，并提供一个平台来快速纠正可能出现的潜在突变 将来。利用 UniRep49 的深度学习，将设计和生成紧密结合的 sACE2 变体 SARS-CoV2-2 刺突蛋白，但不与整合素等内源靶点交叉相互作用 [目标 1]。 同时，我们将进行定向进化来优化尖峰结合并选择 结合内源蛋白 [目标 2]。最后，我们将确定主要候选者并评估耐受性和 工程化 sACE2 变体在小鼠中的免疫原性 [目标 3]。总的来说，该提案将制定 高度特异性的 ACE2 受体模拟物，以便及时创造出免疫原性最小的新型抗病毒药物 拯救生命并预防未来的疫情爆发。 10