The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins.
The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins.
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DOI：
10.3390/ijms21228745
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发表时间：
2020-11-19
影响因子：
5.6
通讯作者：
Garcia A
中科院分区：
文献类型：
--
作者：
Murphy C;Deplazes E;Cranfield CG;Garcia A
他汀类药物是一类用于降低低密度脂蛋白胆固醇的药物，是全球最常用的处方药之一。大多数他汀类药物作为3-羟基-3-甲基-戊二酰辅酶A还原酶（HMGR）的竞争性抑制剂，但他汀类药物对多效性效应的不耐受被认为是由于酶-配体敏感性差而引起的非特异性结合。然而，在过去的几十年里，他汀类药物的理化性质及其与脱靶位点的相互作用的研究进展不大。在这里，我们提出了一个简明的观点，他汀类药物在降低血清胆固醇水平的作用，以及他们如何报告与磷脂膜的相互作用提供了一个重要的洞察机制，一些更常见的观察到的多效性的他汀类药物管理。决定肝选择性的亲脂性与他汀类药物的分子结构直接相关，后者决定了与膜的相互作用和通过膜的转运。因此，他汀类药物的结构是治疗高胆固醇血症的临床重要考虑因素。本文综述了他汀类药物的生物物理学研究和生理学效应的文献，并对他汀类药物多效性的机制原因提供了新的见解，以及了解他汀类药物非胆固醇依赖性效应的前瞻性方法。
Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.
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DOI：
10.3923/jm.2010.833.848
发表时间：
2010-01-01
期刊：
Research Journal of Microbiology
影响因子：
--
作者：
Cabral, M. E.;Delgado, O. D.;Farina, J. I.
通讯作者：
Farina, J. I.
DOI：
10.1073/pnas.77.7.3957
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
ALBERTS, AW;CHEN, J;SPRINGER, J
通讯作者：
SPRINGER, J
影响因子：
37.8
作者：
Bellosta, S;Paoletti, R;Corsini, A
通讯作者：
Corsini, A
影响因子：
3.4
作者：
Bernsdorf, A;Giessmann, T;Siegmund, W
通讯作者：
Siegmund, W
影响因子：
56.9
作者：
BROWN, MS;GOLDSTEIN, JL
通讯作者：
GOLDSTEIN, JL