Broadly neutralizing SARS-CoV-2 peptidic knobs

广泛中和 SARS-CoV-2 肽旋钮

基本信息

批准号：
10735902
负责人：
Vaughn Vasil Smider
金额：
$ 96.72万
依托单位：
APPLIED BIOMEDICAL SCIENCE INSTITUTE
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：
2023-06-09 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735902
关键词：
2019-nCoV Affinity Animals Antibodies Antibody Binding Sites Antibody Response Antigens Antiviral Agents Binding COVID-19 COVID-19 outbreak COVID-19 pandemic Cattle Cessation of life Clinical Combined Modality Therapy Coronavirus Coronavirus spike protein Disease Disease Outbreaks Disease model Distant Disulfides Electron Microscopy Enzyme Inhibition Epitopes Escherichia coli Evolution Fab Immunoglobulins Future G-Protein-Coupled Receptors Genetic Variation Goals HIV Human Immunity Immunize In Vitro Infection Inhalation Ion Channel Length Libraries Light Lung diseases Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Molecular Molecular Evolution Monoclonal Antibodies Organism Parents Passive Immunotherapy Patients Pattern Peptide Hydrolases Peptides Plants Production Property Prophylactic treatment Proteins Resistance Respiratory Disease Risk Rodent Diseases Route SARS coronavirus SARS-CoV-2 variant Serum Severe Acute Respiratory Syndrome Stress System Techniques Technology Therapeutic Therapeutic Monoclonal Antibodies Variant Venoms Viral Viral Physiology Virus Work X-Ray Crystallography coronavirus disease coronavirus pandemic cross reactivity disulfide bond future pandemic glycosylation in vitro activity in vivo inhibitor manufacture microbial nanomolar neutralizing antibody novel novel coronavirus novel drug class novel therapeutics pandemic disease pharmacologic prophylactic severe COVID-19 small molecule targeted treatment therapeutic development tool transmission process variants of concern

项目摘要

Abstract Targeted therapeutic agents range in size from very small organic molecules (100’s of Da) to protein-based molecules like monoclonal antibodies (~150,000 Da). Small disulfide bonded peptides have evolved in many species, including plants and animals, to have ideal pharmacological properties including high affinity target binding, stability to proteases, heat and other stresses. Such peptides include “cyclotides” or “knottins” which can inhibit enzymes, ion channels, and GPCRs with high potency and are often the major active component of venoms of many predator organisms. We have uncovered convergent evolution between ultralong third complementary determining regions (CDR H3s) in the heavy chain of an unusual class of cow antibodies and cyclotide/knottin peptides. We can produce these “knob” peptides in microbial systems and they retain the binding and potency properties of the parent antibody. These tiny peptide-based molecules are small (~4-6 kDa), highly stable, and can bind targets at subnanomolar KD. We have already developed a panel of virus neutralizing knob peptides against SARS-CoV-2 which bind unique epitopes, and some of which maintain high affinity binding to various SARS-CoV-2 variants, including the recent ‘delta’ and ‘omicron’ strains. The high stability, potency, and straightforward manufacturing path enables multiple routes of administration, potentially including inhaled or intranasal delivery, which could be very important prophylactic or treatment in the current or future coronavirus pandemic. Our goals in this project are to further develop the technology to identify peptidic knob domains, expand our panel of knobs against SARS-CoV-2 variants and other coronaviruses like MERS-CoV and SARS-CoV- 1, understand the structural basis of their binding, and validate their activity in vitro and in vivo. The knobs identified here can potentially be used as monotherapy or combination therapy in the current or a new coronavirus pandemic, and will be a valuable new therapeutic class to add to the arsenal against coronavirus disease.

抽象的靶向治疗剂的大小从很小的有机分子（DA的100）到基于蛋白质的分子，例如单克隆抗体（〜150,000 DA）。小二硫键粘合肽在包括植物和动物在内的许多物种中都进化为理想药理特性，包括高亲和力靶标结合，蛋白酶的稳定性，热量和其他压力。这种肽包括可以抑制酶，离子通道和具有高效力的GPCR，通常是毒液的主要活性成分在许多捕食者生物中。我们已经发现了超过三分之一之间的收敛演化不寻常的牛的重链中的互补确定区域（CDR H3S）抗体和环肽/鼻辣椒。我们可以在微生物中生产这些“旋钮”辣椒系统和它们保留了母体抗体的结合和效能。这些小基于肽的分子很小（〜4-6 kDa），高度稳定，可以结合目标亚纳摩尔KD。我们已经开发了一个中和旋钮肽的病毒面板反对结合独特表位的SARS-COV-2，其中一些保持高亲和力与各种SARS-COV-2变体结合，包括最近的“ Delta”和“ Omicron”菌株。高稳定性，效力和直接制造路径可实现多种路线管理，可能包括内部化或鼻内递送，这可能非常重要当前或将来的冠状病毒大流行中的预防或治疗。我们在这个项目中的目标将进一步开发该技术以识别肽旋钮域，扩大我们的面板针对SARS-COV-2变体和其他冠状病毒（如MERS-COV和SARS-COV-）的旋钮 1，了解其结合的结构基础，并在体外和体内验证其活性。此处确定的旋钮可能有可能用作单一疗法或联合疗法当前或新的冠状病毒大流行，将是一个有价值的新治疗类别反对冠状病毒病的武器库。