Redondo-Morata Lorena, Lea Sanford R, Andersen Olaf S, Scheuring Simon
U1006 Institut National de la Santé et de la Recherche Médicale (INSERM), Université Aix-Marseille, Parc Scientifique et Technologique de Luminy, Marseille, France.
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York.
Biophys J. 2016 Jul 26;111(2):363-372. doi: 10.1016/j.bpj.2016.06.016.
Many drugs and other xenobiotics may reach systemic concentrations where they interact not only with the proteins that are their therapeutic targets but also modify the physicochemical properties of the cell membrane, which may lead to altered function of many transmembrane proteins beyond the intended targets. These changes in bilayer properties may contribute to nonspecific, promiscuous changes in membrane protein and cell function because membrane proteins are energetically coupled to their host lipid bilayer. It is thus important, for both pharmaceutical and biophysical reasons, to understand the bilayer-modifying effect of amphiphiles (including therapeutic agents). Here we use atomic force microscopy topography imaging and nanomechanical mapping to monitor the effect of statins, a family of hypolipidemic drugs, on synthetic lipid membranes. Our results reveal that statins alter the nanomechanical stability of the bilayers and increase their elastic moduli depending on the lipid bilayer order. Our results also suggest that statins increase bilayer heterogeneity, which may indicate that statins form nanometer-sized aggregates in the membrane. This is further evidence that changes in bilayer nanoscale mechanical properties may be a signature of lipid bilayer-mediated effects of amphiphilic drugs.
许多药物及其他外源性物质可达到全身浓度，在该浓度下，它们不仅会与作为治疗靶点的蛋白质相互作用，还会改变细胞膜的物理化学性质，这可能导致许多跨膜蛋白的功能发生改变，超出预期靶点。双层膜性质的这些变化可能会导致膜蛋白和细胞功能出现非特异性的、杂乱的变化，因为膜蛋白在能量上与其宿主脂质双层相耦合。因此，出于制药和生物物理两方面的原因，了解两亲分子（包括治疗药物）对双层膜的修饰作用非常重要。在这里，我们使用原子力显微镜形貌成像和纳米力学测绘来监测他汀类药物（一类降血脂药物）对合成脂质膜的影响。我们的结果表明，他汀类药物会改变双层膜的纳米力学稳定性，并根据脂质双层的有序性增加其弹性模量。我们的结果还表明，他汀类药物会增加双层膜的异质性，这可能表明他汀类药物在膜中形成了纳米级聚集体。这进一步证明，双层膜纳米级力学性质的变化可能是两亲性药物脂质双层介导效应的一个特征。
