EVOLVING VIRUS-SPECIFIC sACE2 MIMICS FOR COMPETITIVE INHIBITION OF SARS-CoV-2
EVOLVING VIRUS-SPECIFIC sACE2 MIMICS FOR COMPETITIVE INHIBITION OF SARS-CoV-2
批准号:
10175307
负责人:
Kevin Esvelt
金额:
$39.93万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-01 至 2023-02-28
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
中文摘要
项目总结
英文摘要
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.
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Heritable immunization of the white-footed mouse reservoir of Lyme disease
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批准号:10674208
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项目类别:
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资助金额:$23.51万
-
财政年份:2021
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负责人:Kevin Esvelt
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依托单位:
Heritable immunization of the white-footed mouse reservoir of Lyme disease
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批准号:10677804
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项目类别:
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资助金额:$88.1万
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财政年份:2021
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依托单位:
Heritable immunization of the white-footed mouse reservoir of Lyme disease
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批准号:9989482
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项目类别:
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资助金额:$95.75万
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财政年份:2021
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负责人:Kevin Esvelt
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依托单位:
Developing powerful daisy drive systems for the precise alteration of local populations
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批准号:10085329
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项目类别:
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资助金额:$16.29万
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财政年份:2017
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负责人:Kevin Esvelt
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依托单位:
Sculpting the Enteric Microbiota with CRISPR-Cas Systems
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批准号:9267984
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项目类别:
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资助金额:$24.73万
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财政年份:2016
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负责人:Kevin Esvelt
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依托单位:
Sculpting the Enteric Microbiota with CRISPR-Cas Systems
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批准号:9198068
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项目类别:
-
资助金额:$24.9万
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财政年份:2016
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负责人:Kevin Esvelt
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依托单位:
Sculpting the Enteric Microbiota with CRISPR-Cas Systems
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批准号:8751445
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项目类别:
-
资助金额:$9.0万
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财政年份:2014
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负责人:Kevin Esvelt
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依托单位:
海外基金