Molecularly Engineered Lectins for Intranasal Prophylaxis and Treatment of Coronaviruses

用于鼻内预防和治疗冠状病毒的分子工程凝集素

基本信息

批准号：
10629566
负责人：
David Michael Markovitz
金额：
$ 72.82万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629566
关键词：
2019-nCoV Address Affinity Ambulatory Care Facilities Animal Model Animals Antiviral Agents Atomic Force Microscopy Banana Binding Binding Proteins COVID-19 vaccine Cells Chiroptera Clinical Communities Coronavirus Coronavirus Infections Development Directed Molecular Evolution Dose Ebola Effectiveness Engineering Epidemic Evolution Formulation Future Good Manufacturing Process HIV Half-Life Hamsters Hepatitis C Hepatitis C virus Home Human Immune Immune Tolerance Immune system Immunity Immunocompetent Immunocompromised Host Immunologic Deficiency Syndromes In Vitro Individual Infection Infection prevention Influenza Influenza A virus Influenza B Virus Intranasal Administration Lectin Legal patent Life Light Mannose Mannose Binding Lectin Manufactured Materials Marketing Measles Mediating Membrane Proteins Middle East Respiratory Syndrome Coronavirus Mink Modality Modeling Molecular Molecular Target Monoclonal Antibodies Mus Mutate New Agents Nose Oral Outpatients Parents Pathogenicity Patients Persons Pharmaceutical Preparations Phenotype Polysaccharides Prophylactic treatment Proteins Rattus Resistance Route SARS coronavirus SARS-CoV-2 B.1.1.529 SARS-CoV-2 B.1.617.2 SARS-CoV-2 variant Safety Site Surface Testing Textiles Vaccines Viral Viral Physiology Virus animal coronavirus chimeric antibody clinical implementation coronavirus pandemic coronavirus treatment delivery vehicle efficacy evaluation future epidemic glycosylation hybrid antibody immune activation improved in vivo influenza virus strain large scale production molecular modeling mouse model nanoparticle new outbreak novel coronavirus pandemic potential pathogen prevent prophylactic social social stress stem sugar therapeutic evaluation therapeutically effective uptake viral epidemic viral pandemic

项目摘要

The huge loss of life and major damage to the social fabric that is caused by a viral pandemic has been brought graphically to light with the current SARS-CoV-2 (COVID-19) crisis. Clearly, broad-spectrum antiviral agents that are effective therapeutically and prophylactically against SARS-CoV-2, anticipate other epidemic coronaviruses that emerge from animal reservoirs, and can be administered easily at home or in the outpatient clinic are much needed. Vaccines against SARS-CoV-2 have been remarkably effective, but waning immunity, viral evolution, distribution issues, and social resistance to vaccines have slowed progress. We have created a promising new broad-spectrum anti-coronavirus agent through molecular engineering of a high mannose-binding lectin from bananas, BanLec. The resulting lectin, termed H84T-BanLec (H84T), is the first in which two functions of a lectin have been separated by targeted engineering, leading to loss of mitogenicity (unwanted immune activation) and retention of broad-spectrum antiviral activity; H84T binds to the high mannose on viral envelopes and blocks attachment and fusion to the host cell. We have demonstrated the efficacy of H84T against influenza A and B, HIV, hepatitis C, and Ebola. In mouse (immunocompetent, immunodeficient, and with a humanized immune system), rat, and hamster studies, H84T is well-tolerated. (The selectivity for viruses is based on the fact that high mannose (as opposed to simple mannose) is not present on most healthy animal cells). We have now shown that H84T is effective in vitro against SARS-CoV-2 (including the Omicron variant), SARS-CoV-1, MERS-CoV, and all other coronaviruses tested (all have high mannose on their surface spike protein). H84T is also effective in vivo against MERS-CoV and SARS-CoV-2, the latter whether H84T is delivered systemically or intranasally or as prophylaxis or as therapy. Atomic force microscopy and other modalities reveal that H84T creates multiple, independent, tight bonds with high mannose residues on the spike protein, in keeping with the strong and broad-spectrum antiviral activity. We now propose to further study the mechanism of action and activity of H84T against SARS-CoV-2 variants and coronaviruses from animal reservoirs with pandemic potential. To yet further enhance the potency of H84T and improve large- scale production, we will create and test both molecularly-evolved H84T and H84T-antibody hybrid molecules (“lectibodies”). As the use of H84T as an intranasal agent is likely to be the route by which we can reach many more people, we will optimize formulations for the safe and sustained intranasal release of the molecule. We will further test the therapeutic and prophylactic activity of H84T and derivatives against SARS-CoV-2 variants and emerging coronaviruses in animal models. The development of H84T as an intranasal anti-SARS-CoV-2 drug and pan-coronavirus agent will allow us to provide treatment and/or prophylaxis in coronavirus (and influenza) epidemics using an agent easily administered in the outpatient clinic and even at home so it can reach large numbers of people.

病毒大流行造成了巨大的生命损失和对社会结构的重大破坏显然，广谱抗病毒药物可以应对当前的 SARS-CoV-2 (COVID-19) 危机。对 SARS-CoV-2 以及其他流行性冠状病毒具有有效的治疗和预防作用从动物储存库中产生的、可以在家中或门诊轻松施用的药物有很多针对 SARS-CoV-2 的疫苗非常有效，但免疫力下降、病毒进化，分配问题和社会对疫苗的抵制减缓了我们创造的有希望的进展。通过高甘露糖结合分子工程开发新型广谱抗冠状病毒药物产生的凝集素，称为 H84T-BanLec (H84T)，是第一个含有两种成分的凝集素。凝集素的功能已被靶向工程分离，导致有丝分裂性丧失（不需要的免疫激活）并保留广谱抗病毒活性；H84T 与病毒上的高甘露糖结合；我们已经证明了 H84T 的抗宿主细胞功效。甲型和乙型流感、艾滋病毒、丙型肝炎和埃博拉病毒小鼠（免疫功能正常、免疫缺陷且具有人源化免疫系统）、大鼠和仓鼠研究表明，H84T 具有良好的耐受性。基于大多数健康动物身上不存在高甘露糖（相对于简单甘露糖）的事实我们现已证明 H84T 在体外可有效对抗 SARS-CoV-2（包括 Omicron）。变体）、SARS-CoV-1、MERS-CoV 和所有其他经过测试的冠状病毒（均在其表面含有高甘露糖） H84T 在体内也能有效对抗 MERS-CoV 和 SARS-CoV-2，后者 H84T 是全身给药还是鼻内给药，或者作为预防还是作为治疗。显微镜和其他方式显示 H84T 与高甘露糖形成多重、独立、紧密的键刺突蛋白上的残留物，与强和广谱的抗病毒活性一致。进一步研究H84T针对SARS-CoV-2变种和冠状病毒的作用和活性机制进一步增强 H84T 的效力并改善大流行的可能性。规模生产，我们将创建并测试分子进化的 H84T 和 H84T 抗体杂合分子（“lectibody”），因为使用 H84T 作为鼻内制剂可能是我们能够接触到许多人的途径。更多的人，我们将优化配方，以实现该分子的安全和持续的鼻内释放。进一步测试 H84T 及其衍生物对 SARS-CoV-2 变种的治疗和预防活性， H84T 作为鼻内抗 SARS-CoV-2 药物的开发。泛冠状病毒制剂将使我们能够提供冠状病毒（和流感）的治疗和/或预防使用易于在门诊诊所甚至在家中使用的药剂来控制流行病，因此它可以传播到大范围人数。