Structure-guided and epitope-based design of potent and broadly neutralizing nanobodies for COVID-19 mucosal immunotherapy

用于 COVID-19 粘膜免疫治疗的有效且广泛中和的纳米抗体的结构引导和基于表位的设计

基本信息

项目摘要

Project Summary The coronavirus disease 2019 (COVID-19) rapidly disseminated through the human population and became a global pandemic. Significant efforts have been put into developing vaccines or antibody therapies based on the spike glycoprotein of SARS-CoV-2. One challenge of such strategies is to identify conserved epitopes on the Spike and predict viral mutations that could diminish the effectiveness of the vaccine and immunotherapy. To date, over 20 variant of SARS- CoV-2 genome sequences have been reported. Therefore, structure guided and epitope based design are crucial to generate effective medicines for current and future outbreaks of SARS-CoV- 2 or related coronavirus. Nanobodies can recognize conserved epitopes on hypervariable pathogens. Here, we propose that anti-spike nanobodies can be utilized for rapid identification of protective epitopes to inform design of vaccine and therapeutics. Further, we hypothesize that potent and broadly protective nanobodies against SARS-CoV-2 can be developed as an inhaled prophylactic or therapeutic medicine. In this proposal, we will leverage our complementary strengths through a multi-disciplinary approach combining mucosal immunology, structural biology, and virology, to characterize the molecular interactions and differential specificities of a diverse panel of nanobodies against spike of SARS-CoV-2 and other members of the Betacoronaviruese family (Aim 1). A comprehensive list of conserved and non-conserved epitopes (Aim 2) will be used for structure-based design of potent nanobody multimers for in vivo characterization (Aim 3).
项目概要 2019 年冠状病毒病 (COVID-19) 在人群中迅速传播 并成为全球流行病。已投入大量精力开发疫苗或 基于 SARS-CoV-2 刺突糖蛋白的抗体疗法。其中一项挑战是 策略是识别刺突上的保守表位并预测可能发生的病毒突变 降低疫苗和免疫疗法的有效性。迄今为止,SARS 已有 20 多种变种 已经报道了 CoV-2 基因组序列。因此,结构引导和基于表位的 设计对于生产针对当前和未来 SARS-CoV 爆发的有效药物至关重要 2 或相关冠状病毒。纳米抗体可以识别超变上的保守表位 病原体。在这里,我们建议可以利用抗尖峰纳米抗体来快速识别 保护性表位为疫苗和疗法的设计提供信息。进一步,我们假设 针对 SARS-CoV-2 的有效且具有广泛保护性的纳米抗体可以开发为吸入剂 预防或治疗药物。 在本提案中,我们将通过多学科的合作,利用我们的互补优势 结合粘膜免疫学、结构生物学和病毒学的方法来表征 不同纳米体组针对尖峰的分子相互作用和差异特异性 SARS-CoV-2 和 Betacoronaviruese 家族的其他成员(目标 1)。全面的 保守和非保守表位列表(目标 2)将用于基于结构的设计 用于体内表征的有效纳米抗体多聚体(目标 3)。

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)
Mucosal nanobody IgA as inhalable and affordable prophylactic and therapeutic treatment against SARS-CoV-2 and emerging variants.
  • DOI:
    10.3389/fimmu.2022.995412
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Li, Qi;Humphries, Fiachra;Girardin, Roxie C.;Wallace, Aaron;Ejemel, Monir;Amcheslavsky, Alla;McMahon, Conor T.;Schiller, Zachary A.;Ma, Zepei;Cruz, John;Dupuis, Alan P.;Payne, Anne F.;Maryam, Arooma;Yilmaz, Nese Kurt;McDonough, Kathleen A.;Pierce, Brian G.;Schiffer, Celia A.;Kruse, Andrew C.;Klempner, Mark S.;Cavacini, Lisa A.;Fitzgerald, Katherine A.;Wang, Yang
  • 通讯作者:
    Wang, Yang
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Lisa A Cavacini其他文献

Human Monoclonal Antibodies Protect Neonatal and Adult Rhesus Monkeys from Mucosal or Parenteral Immunodeficiency Virus Exposure
人源单克隆抗体可保护新生和成年恒河猴免受黏膜或胃肠道免疫缺陷病毒暴露
  • DOI:
    10.1203/00006450-199904020-00924
  • 发表时间:
    1999-04-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Timothy W Baba;Vladimir Liska;Regina Hoffman-Lehmann;Josef Vlasak;Marshall R Posner;Lisa A Cavacini;Hermann Katinger;Bruce J Bernacky;Tahir A Rizvi;Michale Keeling;Russell Schmidt;Ruth M Ruprecht
  • 通讯作者:
    Ruth M Ruprecht

Lisa A Cavacini的其他文献

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{{ truncateString('Lisa A Cavacini', 18)}}的其他基金

Structure-guided and epitope-based design of potent and broadly neutralizing nanobodies for COVID-19 mucosal immunotherapy
用于 COVID-19 粘膜免疫治疗的有效且广泛中和的纳米抗体的结构引导和基于表位的设计
  • 批准号:
    10198598
  • 财政年份:
    2021
  • 资助金额:
    $ 69.46万
  • 项目类别:
Structure-guided and epitope-based design of potent and broadly neutralizing nanobodies for COVID-19 mucosal immunotherapy
用于 COVID-19 粘膜免疫治疗的有效且广泛中和的纳米抗体的结构引导和基于表位的设计
  • 批准号:
    10457948
  • 财政年份:
    2021
  • 资助金额:
    $ 69.46万
  • 项目类别:
Mechanism of Potent Neutralization of HIV by IgA CD4i Antibody
IgA CD4i 抗体有效中和 HIV 的机制
  • 批准号:
    8603299
  • 财政年份:
    2013
  • 资助金额:
    $ 69.46万
  • 项目类别:
Mechanism of Potent Neutralization of HIV by IgA CD4i Antibody
IgA CD4i 抗体有效中和 HIV 的机制
  • 批准号:
    9055650
  • 财政年份:
    2013
  • 资助金额:
    $ 69.46万
  • 项目类别:
Mechanism of Potent Neutralization of HIV by IgA CD4i Antibody
IgA CD4i 抗体有效中和 HIV 的机制
  • 批准号:
    8660286
  • 财政年份:
    2013
  • 资助金额:
    $ 69.46万
  • 项目类别:
Arming Neutrophils for the Destruction of HIV by Anti-HIV Antibody
通过抗 HIV 抗体武装中性粒细胞来破坏 HIV
  • 批准号:
    8115249
  • 财政年份:
    2008
  • 资助金额:
    $ 69.46万
  • 项目类别:
Arming Neutrophils for the Destruction of HIV by Anti-HIV Antibody
通过抗 HIV 抗体武装中性粒细胞来破坏 HIV
  • 批准号:
    7552415
  • 财政年份:
    2008
  • 资助金额:
    $ 69.46万
  • 项目类别:
Arming Neutrophils for the Destruction of HIV by Anti-HIV Antibody
通过抗 HIV 抗体武装中性粒细胞来破坏 HIV
  • 批准号:
    7667733
  • 财政年份:
    2008
  • 资助金额:
    $ 69.46万
  • 项目类别:
Arming Neutrophils for the Destruction of HIV by Anti-HIV Antibody
通过抗 HIV 抗体武装中性粒细胞来破坏 HIV
  • 批准号:
    7900402
  • 财政年份:
    2008
  • 资助金额:
    $ 69.46万
  • 项目类别:
Mucosal Protection Against HIV Transmission by Combinations of Anti-HIV Antibodie
通过抗 HIV 抗体组合来预防 HIV 传播的粘膜保护
  • 批准号:
    7500822
  • 财政年份:
    2007
  • 资助金额:
    $ 69.46万
  • 项目类别:

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