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：
Lanying Du
金额：
$ 377.42万
依托单位：
UNIVERSITY OF MINNESOTA
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

来源：
https://reporter.nih.gov/project-details/10522811
关键词：
2019-nCoV Affinity Animal Model Antibodies Antiviral Agents Arenavirus Binding Biological Assay Blood Bolivian Hemorrhagic Fever Virus COVID-19 pandemic COVID-19 therapeutics Cells Chemistry Clinical Complex Coronavirus Cryoelectron Microscopy Cultured Cells Data Development Disease Drug Kinetics Drug Targeting Drug or chemical Tissue Distribution Drug usage Ebola Ebola virus Engineering Epitopes Filovirus Flavivirus Future Glycoproteins Goals Half-Life Human Immunize In Vitro Infection Inhalators Kidney Lassa virus Libraries Lung Mediating Membrane Membrane Fusion Membrane Glycoproteins Midwestern United States Mission Modeling Molecular Weight Mus Names Phage Display Pharmaceutical Preparations Preventive Process Production RNA Viruses Research Safety Series Site Solid Specificity Structure Testing Therapeutic United States National Institutes of Health Validation Variant Viral Virus Virus Diseases Virus Receptors X-Ray Crystallography ZIKA Zika Virus aerosolized base chemical stability cost cost effective drug candidate improved in vivo inhibitor nanobodies novel novel coronavirus pandemic disease pathogenic virus programs rational design receptor binding response screening side effect small molecule small molecule inhibitor structural biology success therapeutic target therapeutically effective viral entry inhibitor virology

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 – 纳米抗体作为流行病病毒的新型进入抑制剂概括纳米抗体 (Nbs) 是源自骆驼科动物纯重链抗体的单域抗体。 Nbs 体积小，作为人类治疗药物，与传统抗体相比具有许多优势，例如它们能够进入目标上的神秘位点、易于生产、卓越的药代动力学以及强大的物理和与小分子药物相比，Nbs 还具有许多优点，例如作为人类治疗药物。由于其高靶向特异性和低副作用，几种铌药物已被临床批准用于治疗。人类疾病，证实了 Nbs 作为人类治疗药物的安全性和有效性。 (CoV) SARS-CoV-2 引起了全球 COVID-19 大流行许多 SARS-CoV-2 的快速出现。与小型药物相比，变体迫切需要有效且广谱的抗 COVID-19 疗法。分子抗病毒药物，NBS 在对抗 SARS-CoV-2 变异体方面特别强大，因为它们可以通过噬菌体展示，可以快速适应新的病毒变种。此外，其他致病病毒也能适应。表现出大流行潜力，例如埃博拉丝状病毒 (EBOV)、拉沙沙粒病毒 (LASV)/Machupo 沙粒病毒 (MACV) 和寨卡黄病毒 (ZIKV) 这些 RNA 病毒均含有表面糖蛋白。介导病毒进入宿主细胞，因此病毒糖蛋白是当前的关键治疗靶点。 AViDD RFA 计划特别将 Nb 抗病毒药物作为其任务之一，因此项目 2。提议开发针对病毒糖蛋白保守表位的高效 Nbs 作为新的在我们之前的研究中，我们开发了几种阻止这些大流行病毒进入的抑制剂。强效抗 CoV Nb，包括一系列名为 Nanosota-1 的抗 SARS-CoV-2 Nb 候选药物。建立了骆驼Nb噬菌体展示库平台，用于Nb筛选，我们追求高Nbs。效力强、稳定性好、生产成本低、副作用小、药代动力学优越、用途广泛抗病毒谱可以开发为新型抗病毒疗法。该项目有三个具体目标。目标 1，我们将使用天然或免疫 Nb 噬菌体展示库筛选抗病毒 Nb。基于结构，体外亲和力成熟优化已发现的 Nbs 的靶标结合亲和力。根据信息，我们将对 Nbs 进行工程设计，以进一步提高其靶标结合亲和力和抗病毒效力。还可以改善 Nb 的药代动力学并尽量减少其副作用。在目标 3 中，我们将测试和验证 Nb。抗病毒感染药物动物模型的候选者该项目是建立在强大的研究团队的基础上的。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，以及行政、化学、结构生物学和病毒学的全力支持项目 2 的总体目标是： (i) 发现针对 SARS 的铌疗法。 CoV-2 及其变体，帮助结束 COVID-19 大流行，并且 (ii) 使 Nbs 成为有效、安全和可靠的针对其他具有大流行潜力的病原病毒的具有成本效益的治疗方法。