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范围从非常小的有机分子（100 Da）到基于蛋白质的分子，如单克隆抗体（~150,000 Da）。肽已经在许多物种（包括植物和动物）中进化，具有理想的药理学特性，包括高亲和力靶标结合、对蛋白酶的稳定性、热和此类肽包括可以抑制酶、离子的“环肽”或“结蛋白”。通道和 GPCR 具有高效力，通常是毒液的主要活性成分我们发现了许多捕食生物之间的趋同进化。一种不寻常的牛的重链中的互补决定区（CDR H3）我们可以在微生物中生产这些“旋钮”肽。系统，它们保留了亲本抗体的结合和效力特性。基于肽的分子很小（~4-6 kDa），高度稳定，并且可以结合靶标我们已经开发了一组病毒中和旋钮肽。对抗 SARS-CoV-2，它结合独特的表位，其中一些表位保持高亲和力与各种 SARS-CoV-2 变体结合，包括最近的“delta”和“omicron”毒株。高稳定性、效力和简单的制造路径使多种途径成为可能给药，可能包括吸入或鼻内给药，这可能非常重要我们在这个项目中的目标是对当前或未来的冠状病毒大流行进行预防或治疗。我们将进一步开发识别肽旋钮结构域的技术，扩大我们的小组针对 SARS-CoV-2 变种和其他冠状病毒（如 MERS-CoV 和 SARS-CoV）的旋钮 1、了解它们结合的结构基础，并验证它们的体外和体内活性。这里确定的旋钮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，并将成为一种有价值的新治疗类别对抗冠状病毒疾病的武器库。