Project 2: Nanobodies as Novel Entry Inhibitors of Pandemic Viruses

项目 2:纳米抗体作为大流行病毒的新进入抑制剂

基本信息

  • 批准号:
    10522811
  • 负责人:
  • 金额:
    $ 377.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-05-16 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Project 2 – Nanobodies as Novel Entry Inhibitors of Pandemic Viruses Summary Nanobodies (Nbs) are single domain antibodies derived from camelid heavy chain-only antibodies. Due to their small size, Nbs have many advantages over conventional antibodies as human therapeutics, such as their access to cryptic sites on targets, ease of production, superior pharmacokinetics, and strong physical and chemical stabilities. Nbs also have many advantages over small molecule drugs as human therapeutics, such as their high on-target specificity and low side effects. Several Nb drugs have been clinically approved to treat diseases in humans, confirming the safety and efficacy of Nbs as human therapeutics. A novel coronavirus (CoV) SARS-CoV-2 has caused the global COVID-19 pandemic. The fast emergence of many SARS-CoV-2 variants calls for urgent need of potent and broad-spectrum anti-COVID-19 therapeutics. Compared to small- molecule antiviral drugs, Nbs are particularly powerful in battling SARS-CoV-2 variants because they can be quickly adapted to new viral variants through phage display. Moreover, other pathogenic viruses also demonstrate pandemic potential, such as Ebola filovirus (EBOV), Lassa arenavirus (LASV)/Machupo arenavirus (MACV), and Zika flavivirus (ZIKV). These RNA viruses all contain a surface glycoprotein that mediates virus entry into host cells, thus the viral glycoprotein serves as a key therapeutic target. The current AViDD RFA program specifically includes Nb antiviral drugs as one of its missions. Therefore, Project 2 proposes to develop highly effective Nbs that target conserved epitopes of viral glycoproteins as novel inhibitors to block viral entry of these pandemic viruses. In our prior studies, we have developed several potent anti-CoV Nbs, including a series of anti-SARS-CoV-2 Nb candidate drugs named Nanosota-1. We have established camelid Nb phage display library platforms for Nb screening. We hypothesize that Nbs with high potency, good stability, low production costs, minimal side effects, superior pharmacokinetics, and broad antiviral spectrum can be developed as novel antiviral therapeutics. This project has three specific aims. In Aim 1, we will screen for antiviral Nbs using naïve or immunized Nb phage display libraries. We will also use in vitro affinity maturation to optimize the target-binding affinity of discovered Nbs. In Aim 2, based on structural information, we will engineer Nbs to further improve their target-binding affinity and antiviral potency. We will also improve Nb’s pharmacokinetics and minimize their side effects. In Aim 3, we will test and validate Nb candidate drugs in animal models against viral infections. This project is built upon a strong research team with complementary expertise in coronaviruses, filoviruses, arenaviruses, and flaviviruses, solid preliminary data, well-established platforms, and full support from the administration, chemistry, structural biology, and virology cores (Cores A and C-E). The overall goals of Project 2 are: (i) to discover Nb therapeutics against SARS- CoV-2 and its variants, helping ending the COVID-19 pandemic and (ii) to establish Nbs as potent, safe, and cost-effective therapeutics against other pathogenic viruses with pandemic potential.
项目2 -纳米抗体作为大流行病毒的新型进入抑制剂 总结 纳米抗体(Nbs)是来源于骆驼科动物仅重链抗体的单结构域抗体。由于 由于其小的尺寸,Nbs作为人类治疗剂具有许多优于常规抗体的优点,例如 它们可接近靶点上的隐蔽位点,易于生产,上级药代动力学,以及强的物理和 化学稳定性NBS作为人类治疗剂也具有许多优于小分子药物的优点, 因为它们的高靶向特异性和低副作用。几种Nb药物已被临床批准用于治疗 在人类疾病中,证实了Nbs作为人类治疗剂的安全性和有效性。新型冠状病毒 (CoV)SARS-CoV-2导致了全球COVID-19大流行。许多SARS-CoV-2的快速出现 因此,迫切需要有效和广谱的抗COVID-19治疗剂。相比之下,小 分子抗病毒药物,Nbs在对抗SARS-CoV-2变种方面特别强大,因为它们可以 通过噬菌体展示快速适应新的病毒变体。此外,其他致病病毒也 显示出大流行潜力,如埃博拉丝状病毒(EBOV)、拉沙沙粒病毒(LASV)/马丘波病毒 沙粒病毒(MACV)和寨卡黄病毒(ZIKV)。这些RNA病毒都含有表面糖蛋白, 介导病毒进入宿主细胞,因此病毒糖蛋白充当关键治疗靶标。当前 AViDD RFA计划特别包括Nb抗病毒药物作为其任务之一。项目2 提出开发靶向病毒糖蛋白的保守表位的高效Nbs作为新的 抑制剂来阻止这些大流行病毒的病毒进入。在我们之前的研究中,我们已经开发了几种 有效的抗CoV Nbs,包括一系列名为Nanosota-1的抗SARS-CoV-2 Nb候选药物。我们有 建立了骆驼科动物Nb噬菌体展示文库平台,用于Nb的筛选。我们假设Nbs高 效力、良好的稳定性、低生产成本、最小的副作用、上级药代动力学和广泛的 抗病毒谱可以开发为新的抗病毒治疗剂。该项目有三个具体目标。在 目的1:利用天然或免疫的噬菌体展示文库筛选抗病毒的Nbs。我们还将在 体外亲和力成熟以优化发现的Nbs的靶结合亲和力。在目标2中,基于结构 根据这些信息,我们将对Nbs进行工程改造,以进一步提高其靶向结合亲和力和抗病毒效力。我们将 还改善Nb的药代动力学并最小化其副作用。在目标3中,我们将测试和验证Nb 候选药物在动物模型中对抗病毒感染。该项目是建立在一个强大的研究团队, 冠状病毒、丝状病毒、沙粒病毒和黄病毒方面的互补专业知识,可靠的初步数据, 完善的平台,以及来自管理、化学、结构生物学和病毒学的全力支持 核心(核心A和C-E)。项目2的总体目标是:(i)发现抗SARS的Nb疗法- CoV-2及其变体,帮助结束COVID-19大流行,以及(ii)建立Nbs作为有效,安全, 针对具有大流行潜力的其他病原性病毒的具有成本效益的疗法。

项目成果

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Lanying Du其他文献

Lanying Du的其他文献

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{{ truncateString('Lanying Du', 18)}}的其他基金

Rational design and evaluation of novel mRNA vaccines against MERS-CoV
针对 MERS-CoV 的新型 mRNA 疫苗的合理设计和评估
  • 批准号:
    10335159
  • 财政年份:
    2021
  • 资助金额:
    $ 377.42万
  • 项目类别:
Rational design and evaluation of novel mRNA vaccines against MERS-CoV
针对 MERS-CoV 的新型 mRNA 疫苗的合理设计和评估
  • 批准号:
    10410839
  • 财政年份:
    2021
  • 资助金额:
    $ 377.42万
  • 项目类别:
Structure-based design of coronavirus subunit vaccines
基于结构的冠状病毒亚单位疫苗设计
  • 批准号:
    10397563
  • 财政年份:
    2021
  • 资助金额:
    $ 377.42万
  • 项目类别:
Structure-based design of coronavirus subunit vaccines
基于结构的冠状病毒亚单位疫苗设计
  • 批准号:
    10415747
  • 财政年份:
    2021
  • 资助金额:
    $ 377.42万
  • 项目类别:
Novel nanobodies to prevent and treat SARS-CoV-2 and other pathogenic human coronaviruses
用于预防和治疗 SARS-CoV-2 和其他致病性人类冠状病毒的新型纳米抗体
  • 批准号:
    10411118
  • 财政年份:
    2020
  • 资助金额:
    $ 377.42万
  • 项目类别:
Novel nanobodies to prevent and treat SARS-CoV-2 and other pathogenic human coronaviruses
用于预防和治疗 SARS-CoV-2 和其他致病性人类冠状病毒的新型纳米抗体
  • 批准号:
    10168173
  • 财政年份:
    2020
  • 资助金额:
    $ 377.42万
  • 项目类别:
Novel nanobodies to prevent and treat SARS-CoV-2 and other pathogenic human coronaviruses
用于预防和治疗 SARS-CoV-2 和其他致病性人类冠状病毒的新型纳米抗体
  • 批准号:
    10662297
  • 财政年份:
    2020
  • 资助金额:
    $ 377.42万
  • 项目类别:
Novel nanobodies to prevent and treat SARS-CoV-2 and other pathogenic human coronaviruses
用于预防和治疗 SARS-CoV-2 和其他致病性人类冠状病毒的新型纳米抗体
  • 批准号:
    10456313
  • 财政年份:
    2020
  • 资助金额:
    $ 377.42万
  • 项目类别:
A novel and effective nanobody to prevent and treat Zika virus infection
一种预防和治疗寨卡病毒感染的新型有效纳米抗体
  • 批准号:
    9920081
  • 财政年份:
    2019
  • 资助金额:
    $ 377.42万
  • 项目类别:
Structure-based design of coronavirus subunit vaccines
基于结构的冠状病毒亚单位疫苗设计
  • 批准号:
    9914088
  • 财政年份:
    2018
  • 资助金额:
    $ 377.42万
  • 项目类别:

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