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，其患病率令人震惊。这特别具有挑战性治疗持续的AF并使用目前可用的抗心律失常学恢复正常的窦性心律。因此，新颖的离子开发下一代抗心律失常药物治疗需要的渠道阻塞方式持续的AF。长期纤颤的心房中重塑的标志是存在组成型活跃，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）。组成性活跃的IKACH充当背景向内整流器电导，可以有助于缩短心房有效性难治时期，因此对AF的持久性。我们之前证明了Ikach与肽毒素tertiapinq，一种21-氨基酸合成肽阻滞剂，最初是从欧洲蜜蜂中分离出来的毒液，终止持续的AF。因此，我们对生物工程，生产和表征了一种小说和潜在的Ikach阻塞 peptibody。肽是嵌合体作为碎片的融合蛋白，可结晶的人类的融合蛋白具有生物活性“弹头”肽的免疫球蛋白G（IgG1）。肽结合了A的生物学/治疗活性给定的胡椒，具有单克隆抗体的稳定性，并且是稳定且安全的分子，它们正在生存临床疗法。我们的IKACH阻断肽是在人IgG1的FC片段之间构造的和tertiapinq通过八甘氨酸垫片连接在一起。在此应用程序中，我们建议检验以下假设。设计为Ikach的潜在和生物活性阻滞剂的生物工程辣椒在持续的AF中是抗心律失常。我们的目标为：1-描绘ikach的胡椒块的结构决定者； 2-确定心房特异性，抗ikach肽的电生理安全和治疗潜力在持续的AF模型中；和3至生物工程师的下一代肽增加了IKACH效力和特异性。成功成就我们的建议应该是急需的刻意，创新和合理发展的重要一步，基于生物工程方法的有效抗颤音剂，其针对在机理中很重要的离子通道一种主要的心脏病。