Peptibodies As Novel Therapies in Atrial Fibrillation

肽体作为心房颤动的新疗法

基本信息

批准号：
10598711
负责人：
Jose S Jalife
金额：
$ 62.06万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
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：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598711
关键词：
Acetylcholine Action Potentials Address Affect Amino Acids Anti-Arrhythmia Agents Arrhythmia Atrial Fibrillation Avidity Biological Biomedical Engineering Cardiac Cells Chimera organism Chimeric Proteins Chronic Clinic Clinical Dangerousness Data Development Electrophysiology (science)European Frequencies Genomics Goals Heart Heart Atrium Heart Diseases Human Immune Immunoglobulin Fragments Immunoglobulin G In Vitro Ion Channel Length Libraries Link Maps Modality Molecular Monoclonal Antibodies Morbidity - disease rate Mus Muscle Cells Mutation Myopathy Optics Peptides Perfusion Pharmacotherapy Potassium Prevalence Protein Engineering Protein Fragment Proteomics Refractory Rodent Safety Sinus Specificity Structure Testing Therapeutic Therapeutic Effect Thrombocytopenic Purpura Thrombopoietin Variant Venoms Ventricular Yeasts aged design epigenomics experimental study heart rhythm in vivo in vivo evaluation inhibitor innovation mortality mutant next generation novel novel therapeutics patch clamp peptidomimetics porcine model prevent side effect structural determinants synthetic peptide

项目摘要

ABSTRACT Atrial fibrillation (AF) is the most common arrhythmia and its prevalence is rising alarmingly. It is particularly challenging to treat persistent AF and to restore normal sinus rhythm with currently available antiarrhythmics. Therefore, novel ion channel blocking modalities are needed for the development of the next generation of antiarrhythmic pharmacotherapies in persistent AF. A hallmark of remodeling in the chronically fibrillating atria is the presence of a constitutively active, parasympathetic stimulation independent acetylcholine sensitive inward rectifier potassium current (IKACh). Constitutively active IKACh acts as a background inward rectifier conductance and can contribute to the shortening of the atrial effective refractory period, and consequently to the perpetuation of AF. We demonstrated earlier that IKACh blockade with the peptidotoxin tertiapinQ, a 21-amino acid synthetic peptide blocker of IKACh originally isolated from the European honeybee venom, terminates persistent AF. We thus bioengineered, produced and characterized a novel, and potent IKACh blocking peptibody. Peptibodies are chimeras generated as fusion proteins of the fragment crystallizable (Fc) domain of the human immunoglobulin G (IgG1) with a bioactive “warhead” peptide. Peptibodies combine the biologic/therapeutic activity of a given peptide, with the stability of monoclonal antibodies and are stable and safe molecules that are emerging as viable clinical therapies. Our IKACh blocking peptibody was constructed as a fusion protein between the Fc fragment of human IgG1 and tertiapinQ linked together by an octaglycine spacer. In this application, we propose to test the hypothesis that bioengineered peptibodies designed as potent and bioactive blockers of IKACh are antiarrhythmic in persistent AF. Our goals are: 1- to delineate the structural determinants for the peptibody’s block of IKACh; 2- to determine the atrial specificity, electrophysiological safety and therapeutic potential of anti-IKACh peptibodies in a pig model of persistent AF; and 3- to bioengineer next generation peptibodies that have increased IKACh potency and specificity. Successful accomplishment of our proposal should be a major step forward in the deliberate, innovative, and rational development of much needed and effective antifibrillatory agents based on bioengineering approaches that target ion channels important in the mechanism of a major cardiac disease.

抽象的心房颤动（AF）是最常见的心律失常，其患病率正在惊人地上升，这尤其具有挑战性。用目前可用的抗心律失常药物治疗持续性房颤并恢复正常窦性心律。开发下一代抗心律失常药物疗法需要通道阻断方式慢性颤动心房重塑的一个标志是持续性房颤的存在。副交感神经刺激独立的乙酰胆碱敏感的内向整流钾电流（IKACh）。活跃的 IKACh 充当背景内向整流器电导，有助于缩短心房有效性我们之前证明了 IKACh 阻断作用。肽毒素 tertiapinQ，一种 21 个氨基酸合成的 IKACh 肽阻断剂，最初从欧洲蜜蜂中分离出来因此，我们通过生物工程设计、生产并表征了一种新型、有效的 IKACh 阻断剂。肽体是作为人类可结晶片段 (Fc) 结构域的融合蛋白产生的嵌合体。免疫球蛋白 G (IgG1) 与生物活性“弹头”肽结合了生物/治疗活性。给定的肽，具有单克隆抗体的稳定性，是稳定和安全的分子，正在成为可行的我们的 IKACh 阻断肽体是作为人 IgG1 Fc 片段之间的融合蛋白构建的。和 tertiapinQ 通过八甘氨酸间隔基连接在一起在本申请中，我们建议检验以下假设：生物工程肽体设计为 IKACh 的有效生物活性阻断剂，可有效治疗持续性 AF。是： 1- 描绘 IKACh 肽体阻断的结构决定因素； 2- 确定心房特异性，抗 IKACh 肽体在持续性 AF 猪模型中的电生理安全性和治疗潜力；以及 3-to 生物工程下一代肽体提高了 IKACh 的效力和特异性。我们的建议应该是在深思熟虑、创新和合理发展急需的和基于生物工程方法的有效抗颤药物，针对在机制中重要的离子通道一种主要的心脏病。