转甲状腺素稳定剂的不同结合亲和力和动力学。

IF 2.2 4区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS
Alan X Ji, Andreas Betz, Uma Sinha
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引用次数: 0

摘要

转甲状腺素淀粉样心肌病(atr - cm)是一种进行性、致命性疾病。四聚体转甲状腺素(TTR)解离是致病机制中的触发事件;破坏稳定的TTR突变加速了这一过程。TTR稳定剂他法米底斯和acoramidis是FDA批准的唯一治疗atr - cm的药物。通过模仿超稳定的疾病保护变体T119M的稳定特性,我们假设acoramidis与其他TTR稳定剂(如他法米底斯和双氟尼拉)相比,表现出不同的TTR结合、动力学稳定性和四聚体稳定性。采用表面等离子体共振(SPR)和微尺度热电泳(MST)评价了acoramidis和tafamidis的TTR结合亲和力和TTR相互作用的热力学稳定性。采用免疫斑点法测定血浆蛋白抗酸性变性作用下,acoramidis、tafamidis和di氟尼柳对四聚体TTR的稳定作用。在动力学研究中,SPR表明,与他法米底斯相比,acoramidis与TTR结合的停留时间长4倍。解离常数与MST平衡测量结果一致。用MST测定,acoramidis对纯化的TTR的亲和力是tafamidis的4倍。当在临床相关的血浆浓度下测试时,acoramidis稳定TTR抗酸性变性的程度(≥90%)远高于他非他脒或双氟尼拉。值得注意的是,他法米地和双氟尼拉均表现出四聚体TTR的部分稳定。与其他稳定剂相比,acoramidis在TTR结合亲和力、动力学稳定性和酸介导变性方面具有更强的作用。这些特性可能有助于acoramidis实现血浆样品中TTR的近乎完全稳定。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Differential Binding Affinities and Kinetics of Transthyretin Stabilizers.

Differential Binding Affinities and Kinetics of Transthyretin Stabilizers.

Differential Binding Affinities and Kinetics of Transthyretin Stabilizers.

Differential Binding Affinities and Kinetics of Transthyretin Stabilizers.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Dissociation of tetrameric transthyretin (TTR) is the triggering event in the pathogenic mechanism; destabilizing TTR mutations accelerate the process. The TTR stabilizers, tafamidis and acoramidis, are the only FDA approved treatments for patients with ATTR-CM. By mimicking the stabilizing characteristics of the super-stabilizing, disease-protecting variant T119M, we hypothesize that acoramidis displays differential TTR binding, kinetic stability, and tetramer stabilization compared with other TTR stabilizers, such as tafamidis and diflunisal. The TTR binding affinity and thermodynamic stability of TTR interaction of acoramidis and tafamidis were assessed by surface plasmon resonance (SPR) and microscale thermophoresis (MST). Tetrameric TTR stabilization by acoramidis, tafamidis, and diflunisal in the presence of plasma proteins against acidic denaturation was measured by immune blots. In kinetic studies, SPR demonstrated 4 times longer residence time for acoramidis bound to TTR compared with tafamidis. The dissociation constants were consistent with those determined by equilibrium measurements in MST. The affinity of acoramidis for purified TTR, as measured by MST, was 4 times higher than that of tafamidis. When tested at clinically relevant plasma concentrations, acoramidis stabilized TTR against acidic denaturation to a much higher extent (≥90%) than tafamidis or diflunisal. Of note, both tafamidis and diflunisal demonstrated partial stabilization of tetrameric TTR. Relative to other stabilizers, acoramidis is more potent as independently assessed by TTR binding affinity, kinetic stability, and acid-mediated denaturation. These properties may contribute to the ability of acoramidis to achieve near-complete stabilization of TTR in plasma samples.

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来源期刊
CiteScore
5.10
自引率
3.30%
发文量
367
审稿时长
1 months
期刊介绍: Journal of Cardiovascular Pharmacology is a peer reviewed, multidisciplinary journal that publishes original articles and pertinent review articles on basic and clinical aspects of cardiovascular pharmacology. The Journal encourages submission in all aspects of cardiovascular pharmacology/medicine including, but not limited to: stroke, kidney disease, lipid disorders, diabetes, systemic and pulmonary hypertension, cancer angiogenesis, neural and hormonal control of the circulation, sepsis, neurodegenerative diseases with a vascular component, cardiac and vascular remodeling, heart failure, angina, anticoagulants/antiplatelet agents, drugs/agents that affect vascular smooth muscle, and arrhythmias. Appropriate subjects include new drug development and evaluation, physiological and pharmacological bases of drug action, metabolism, drug interactions and side effects, application of drugs to gain novel insights into physiology or pathological conditions, clinical results with new and established agents, and novel methods. The focus is on pharmacology in its broadest applications, incorporating not only traditional approaches, but new approaches to the development of pharmacological agents and the prevention and treatment of cardiovascular diseases. Please note that JCVP does not publish work based on biological extracts of mixed and uncertain chemical composition or unknown concentration.
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