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.

已经带来了巨大的生命损失和对由病毒大流行造成的社会结构的重大破坏以图形方式与当前的SARS-COV-2（COVID-19）危机有关。显然，广阔的抗病毒药物对SARS-COV-2具有有效的治疗性和预防性，预期其他流行病病毒从动物水库中出来的，可以在家里或门诊诊所轻松管理需要。针对SARS-COV-2的疫苗非常有效，但是免疫学，病毒进化，分销问题和对疫苗的社会抵抗已经放缓进度。我们已经建立了一个诺言通过高甘露糖结合的分子工程，新的宽光谱抗科罗纳病毒剂来自Banlec的香蕉的凝集素。由此产生的讲座，称为H84T-Banlec（H84T），是第一个两个讲座的功能已通过有针对性的工程分开，导致丝裂性丧失（不需要免疫激活）和宽光谱抗病毒活性的保留； H84T与病毒上的高甘露糖结合信封和阻断宿主细胞的附件和融合。我们已经证明了H84T的效率流感A和B，HIV，丙型肝炎和埃博拉病毒。在小鼠中（免疫能力，免疫缺陷，并具有人源化的免疫培训），大鼠和仓鼠研究，H84T耐受良好。（病毒的选择性是基于大多数健康动物不存在高甘露糖（而不是简单的甘露糖）的事实细胞）。我们现在已经表明，H84T在体外对SARS-COV-2有效（包括Omicron 变体），SARS-COV-1，MERS-COV和所有其他测试的冠状病毒（所有冠状病毒均具有高甘露糖表面峰值蛋白）。 H84T在体内也对MERS-COV和SARS-COV-2有效，后者有效 H84T是全身或鼻内或预防或作为治疗的。原子力显微镜和其他方式表明，H84T与高甘露糖产生多个独立的紧密键峰值蛋白上的残基与强和宽光谱的抗病毒活性保持一致。我们现在提出进一步研究H84T对SARS-COV-2变体和冠状病毒的作用机理和活性来自具有大流行潜力的动物储层。为了进一步提高H84T的效力并提高了大型量表产生，我们将创建和测试分子发展的H84T和H84T抗体混合分子（“束请”）。因为将H84T用作鼻内剂可能是我们可以到达许多人的路线更多人，我们将优化公式，以确保分子的安全和持续的鼻内释放。我们将进一步测试H84T和衍生物针对SARS-COV-2变体的治疗和预防活性动物模型中新兴的冠状病毒。 H84T作为鼻内抗SARS-COV-2药物的发展泛氧化病毒剂将使我们能够在冠状病毒（和actractza）中提供治疗和/或预防情节使用在门诊诊所中轻松管理的代理，甚至在家中，以便可以达到大的人数。