Tsuchiya Hironori, Mizogami Maki
Asahi University School of Dentistry, Mizuho, Gifu - Japan.
Department of Anesthesiology, Kizawa Memorial Hospital, Minokamo, Gifu - Japan.
Drug Target Insights. 2020 Dec 22;14:34-47. doi: 10.33393/dti.2020.2185. eCollection 2020.
Plasma membranes are not the homogeneous bilayers of uniformly distributed lipids but the lipid complex with laterally separated lipid raft membrane domains, which provide receptor, ion channel and enzyme proteins with a platform. The aim of this article is to review the mechanistic interaction of drugs with membrane lipid rafts and address the question whether drugs induce physicochemical changes in raft-constituting and raft-surrounding membranes.
Literature searches of PubMed/MEDLINE and Google Scholar databases from 2000 to 2020 were conducted to include articles published in English in internationally recognized journals. Collected articles were independently reviewed by title, abstract and text for relevance.
The literature search indicated that pharmacologically diverse drugs interact with raft model membranes and cellular membrane lipid rafts. They could physicochemically modify functional protein-localizing membrane lipid rafts and the membranes surrounding such domains, affecting the raft organizational integrity with the resultant exhibition of pharmacological activity. Raft-acting drugs were characterized as ones to decrease membrane fluidity, induce liquid-ordered phase or order plasma membranes, leading to lipid raft formation; and ones to increase membrane fluidity, induce liquid-disordered phase or reduce phase transition temperature, leading to lipid raft disruption.
Targeting lipid raft membrane domains would open a new way for drug design and development. Since angiotensin-converting enzyme 2 receptors which are a cell-specific target of and responsible for the cellular entry of novel coronavirus are localized in lipid rafts, agents that specifically disrupt the relevant rafts may be a drug against coronavirus disease 2019.
质膜并非由均匀分布的脂质构成的同质双层膜，而是具有横向分离的脂筏膜结构域的脂质复合体，这些结构域为受体、离子通道和酶蛋白提供了一个平台。本文旨在综述药物与膜脂筏的作用机制，并探讨药物是否会引起构成脂筏及围绕脂筏的膜发生物理化学变化这一问题。
对2000年至2020年期间PubMed/MEDLINE和谷歌学术数据库进行文献检索，纳入在国际知名期刊上发表的英文文章。对收集到的文章，独立根据标题、摘要和正文进行相关性审查。
文献检索表明，药理性质各异的药物与脂筏模型膜和细胞膜脂筏相互作用。它们可通过物理化学方式改变定位有功能蛋白的膜脂筏及其周围的膜，影响脂筏的组织完整性，从而表现出药理活性。作用于脂筏的药物可分为两类：一类是降低膜流动性、诱导液晶有序相或使质膜有序化，从而导致脂筏形成；另一类是增加膜流动性、诱导液晶无序相或降低相变温度，从而导致脂筏破坏。
靶向脂筏膜结构域将为药物设计和开发开辟一条新途径。由于血管紧张素转换酶2受体作为新型冠状病毒细胞特异性靶点并负责其细胞内进入，定位于脂筏中，因此特异性破坏相关脂筏的药物可能是一种抗2019冠状病毒病的药物。
