金刚烷胺,一种由金刚烷骨架和氨基组成的小型两性有机化合物,在1963年首次被确认为抗病毒药物,并于1976年获得预防A型流感病毒的批准。从那以后,它也被用于治疗帕金森病相关的运动障碍,并被认为是治疗冠状病毒。由于金刚烷胺通常靶向膜结合蛋白,它与膜的相互作用被认为是重要的。生物膜现在被广泛理解为是横向异质的,并且已知某些蛋白质优先共定位在特定的脂质结构域内。Amanta-dine,因此,优先定位在某些脂质组成域?为了解决这个问题,我们研究了金刚烷胺与胆固醇组成的相分离膜的相互作用,DSPC(1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱),POPC(1-棕榈酰-2-油酰基-甘油-3-磷酸胆碱),和DOPC(1,2-二油酰基-sn-甘油-3-磷酸胆碱),以及单相DPhPC(1,2-二植酸酰-sn-甘油-3-磷-磷胆碱)膜。从朗缪尔槽和差示扫描量热(DSC)测量,我们决定,分别,金刚烷胺优先与紊乱的脂质结合,如POPC,并降低POPC/DSPC/胆固醇混合物的相变温度,暗示金刚烷胺会增加细胞膜紊乱.Further,使用液滴界面双层(DIBs),我们观察到金刚烷胺破坏DPhPC膜,与其无序能力一致。我们还在具有不同量的金刚烷胺的POPC/DSPC/胆固醇膜上进行了分子动力学(MD)模拟。与实验一致,MD模拟显示金刚烷胺更喜欢与无序联系,POPC丰富的域,do-主要边界,和脂质甘油骨架。由于不同的蛋白质与不同的脂质结构域共定位,我们的结果可能对哪一类蛋白质可能提供更好的金刚烷胺靶标有影响.
Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson\'s disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, we studied amantadine\'s interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.