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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，以图表的形式来说明当前的SARS-CoV-2（COVID-19）危机。显然，广谱抗病毒剂，对SARS-CoV-2有治疗和预防作用，从动物宿主中产生，并且可以在家中或门诊部轻松管理的药物， needed.针对SARS-CoV-2的疫苗非常有效，但免疫力减弱，病毒进化，分配问题和社会对疫苗的抵制减缓了进展。我们创造了一个有希望的通过高甘露糖结合的分子工程的新的广谱抗冠状病毒剂香蕉凝集素BanLec。所得到的凝集素，称为H84 T-BanLec（H84 T），是第一个在其中两个凝集素的功能已经通过靶向工程化分离，导致有丝分裂原性的丧失（不需要的 H84 T结合病毒表面的高甘露糖，包裹并阻断与宿主细胞的附着和融合。我们已经证明了H84 T对甲型和B型流感、艾滋病毒、丙型肝炎和埃博拉病毒。在小鼠（免疫活性、免疫缺陷和人源化免疫系统）、大鼠和仓鼠研究中，H84 T耐受良好。(The对病毒的选择性基于大多数健康动物不存在高甘露糖（与简单甘露糖相反细胞）。我们现在已经证明H84 T在体外对SARS-CoV-2（包括Omicron）有效变异体）、SARS-CoV-1、MERS-CoV和所有其他测试的冠状病毒（它们的表面刺突蛋白）。H84 T在体内也有效地对抗MERS-CoV和SARS-CoV-2，后者无论H84 T是全身还是鼻内递送，还是作为预防或治疗。原子力显微镜和其他方法显示，H84 T与高甘露糖产生多个独立的紧密结合，刺突蛋白上的氨基酸残基，与强而广谱的抗病毒活性一致。我们现建议进一步研究H84 T抗SARS-CoV-2变异株和冠状病毒的作用机制和活性从有传染性的动物宿主中为了进一步增强H84 T的效力并改善大- 规模生产，我们将创造和测试分子进化的H84 T和H84 T-抗体杂交分子（“lectibodies”）。由于使用H84 T作为鼻内药物可能是我们可以达到许多目的的途径，更多的人，我们将优化配方的安全和持续的鼻内释放的分子。我们将进一步测试H84 T及其衍生物对SARS-CoV-2变异体的治疗和预防活性，动物模型中的新型冠状病毒。H84 T鼻内抗SARS-CoV-2药物的研究进展和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/或预防使用一种在门诊诊所甚至在家里容易施用的药剂来预防流行病，人数。