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
基本信息
- 批准号:10175307
- 负责人:
- 金额:$ 39.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:2019-nCoVAffectAffinityAlbuminsAntiviral AgentsBindingBinding ProteinsBiologicalBiological AssayCOVID-19 pandemicCellsClinicalClinical TrialsCommunicable DiseasesDataDirected Molecular EvolutionDisease OutbreaksDoseEffectivenessEngineeringEvolutionExhibitsFutureGenerationsGoalsHumanHuman bodyIntegrin BindingIntegrinsLaboratoriesLeftLibrariesMachine LearningMedicineMusMutationPathogenicityPatientsProcessProteinsRecombinantsSafetySignal TransductionTherapeuticTimeToxic effectTrainingVariantViralVirusVirus DiseasesVirus Inhibitorsbasecombatcross reactivitydeep learningdesignglobal health emergencyimmunogenicityimprovedin vivoinhibitor/antagonistlead candidatemutantnovelnovel therapeuticspreventreceptorside effect
项目摘要
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
项目摘要
高致病性的新型SARS冠状病毒2(SARS-CoV-2)的快速传播引起了全球范围的关注,
健康紧急情况。因此,迫切需要有效的抗病毒治疗剂来对抗这种病毒。
SARS-CoV-2病毒通过结合病毒刺突蛋白2的ACE 2受体1进入细胞。在其
可溶性形式的ACE 2(sACE 2)具有用作稳定的和非免疫原性的竞争性ACE抑制剂的潜力。
SARS-CoV-2的抑制剂,目前正在临床试验中探索3。由于潜在的负面影响
抗尖峰单克隆抗体的作用18,以及ACE 2表现出其他生物学作用的事实4 -6,包括整合素
信号调节7,8,刺突特异性受体模拟物将产生新的治疗SARS-CoV-2和
其他潜在的高传染性疾病。
该提案寻求使用机器学习和定向进化来开发高亲和力,
内源性无活性的sACE 2模拟物,以创造快速可实施的治疗方法,
SARS-CoV-2和潜在的冠状病毒。这种方法将允许生成可扩展的
可翻译的生物制剂,并提供一个平台,以快速纠正可能出现的潜在突变
在未来利用UniRep 49的深度学习,将设计和生成紧密结合的sACE 2变体
SARS-CoV 2 -2刺突蛋白,但不与内源性靶点如整联蛋白交叉相互作用[目的1]。
同时,我们将进行定向进化以优化尖峰结合,并选择
结合内源性蛋白[目的2]。最后,我们将确定主要候选人,并评估耐受性,
小鼠中工程化sACE 2变体的免疫原性[目的3]。总的来说,这一建议将发展
高特异性ACE 2受体模拟物,以便及时产生具有最小免疫原性的新型抗病毒药物
以挽救生命并防止未来的疫情爆发。
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项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kevin Esvelt其他文献
Kevin Esvelt的其他文献
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{{ truncateString('Kevin Esvelt', 18)}}的其他基金
Heritable immunization of the white-footed mouse reservoir of Lyme disease
白足小鼠莱姆病储库的遗传免疫
- 批准号:
10674208 - 财政年份:2021
- 资助金额:
$ 39.93万 - 项目类别:
Heritable immunization of the white-footed mouse reservoir of Lyme disease
白足小鼠莱姆病储库的遗传免疫
- 批准号:
10677804 - 财政年份:2021
- 资助金额:
$ 39.93万 - 项目类别:
Heritable immunization of the white-footed mouse reservoir of Lyme disease
白足小鼠莱姆病储库的遗传免疫
- 批准号:
9989482 - 财政年份:2021
- 资助金额:
$ 39.93万 - 项目类别:
Developing powerful daisy drive systems for the precise alteration of local populations
开发强大的雏菊驱动系统以精确改变当地人口
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10085329 - 财政年份:2017
- 资助金额:
$ 39.93万 - 项目类别:
Sculpting the Enteric Microbiota with CRISPR-Cas Systems
使用 CRISPR-Cas 系统塑造肠道微生物群
- 批准号:
9267984 - 财政年份:2016
- 资助金额:
$ 39.93万 - 项目类别:
Sculpting the Enteric Microbiota with CRISPR-Cas Systems
使用 CRISPR-Cas 系统塑造肠道微生物群
- 批准号:
9198068 - 财政年份:2016
- 资助金额:
$ 39.93万 - 项目类别:
Sculpting the Enteric Microbiota with CRISPR-Cas Systems
使用 CRISPR-Cas 系统塑造肠道微生物群
- 批准号:
8751445 - 财政年份:2014
- 资助金额:
$ 39.93万 - 项目类别:
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