Cao Ping, Dou Guifang, Cheng Yuanguo, Che Jinjing
Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, Beijing, People's Republic of China.
Beijing Institute of Microbiology and Epidemiology, Beijing, People's Republic of China.
PLoS One. 2017 Feb 16;12(2):e0171567. doi: 10.1371/journal.pone.0171567. eCollection 2017.
Most mechanistic studies on human immunodeficiency virus (HIV) peptide fusion inhibitors have focused on the interactions between fusion inhibitors and viral envelope proteins. However, the interactions of fusion inhibitors with viral membranes are also essential for the efficacy of these drugs. Here, we utilized surface plasmon resonance (SPR) technology to study the interactions between the HIV fusion inhibitor peptides sifuvirtide and enfuvirtide and biomembrane models. Sifuvirtide presented selectivity toward biomembrane models composed of saturated dipalmitoylphosphatidylcholine (DPPC) (32-fold higher compared with unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine [POPC]) and sphingomyelin (SM) (31-fold higher compared with POPC), which are rigid compositions enriched in the HIV viral membrane. In contrast, enfuvirtide showed no significant selectively toward these rigid membrane models. Furthermore, the bindings of sifuvirtide and enfuvirtide to SM bilayers were markedly higher than those to monolayers (14-fold and 23-fold, respectively), indicating that the inner leaflet influences the binding of these drugs to SM bilayers. No obvious differences were noted in the bindings of either peptide to the other mono- and bilayer models tested, illustrating that both peptides interact with these membranes through surface-binding. The bindings of the inhibitor peptides to biomembranes were found to be driven predominantly by hydrophobic interactions rather than electrostatic interactions, as determined by comparing their affinities to those of positively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (EPC) to zwitterionic membrane models. The improved efficiency of sifuvirtide relative to enfuvirtide might be related to its ability to adsorb on rigid lipidic areas, such as the viral envelope and lipid rafts, which results in an increased sifuvirtide concentration at the fusion site.
大多数关于人类免疫缺陷病毒（HIV）肽融合抑制剂的机制研究都集中在融合抑制剂与病毒包膜蛋白之间的相互作用上。然而，融合抑制剂与病毒膜的相互作用对于这些药物的疗效也至关重要。在此，我们利用表面等离子体共振（SPR）技术研究了HIV融合抑制剂肽西夫韦肽和恩夫韦肽与生物膜模型之间的相互作用。西夫韦肽对由饱和二棕榈酰磷脂酰胆碱（DPPC）组成的生物膜模型具有选择性（与不饱和的1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱[POPC]相比高32倍），对鞘磷脂（SM）也具有选择性（与POPC相比高31倍），这两种成分在HIV病毒膜中含量丰富且结构刚性。相比之下，恩夫韦肽对这些刚性膜模型没有明显的选择性。此外，西夫韦肽和恩夫韦肽与SM双层膜的结合明显高于与单层膜的结合（分别高14倍和23倍），表明内膜层会影响这些药物与SM双层膜的结合。在测试的这两种肽与其他单层和双层膜模型的结合中未观察到明显差异，说明这两种肽都是通过表面结合与这些膜相互作用的。通过比较抑制剂肽与带正电荷的1-棕榈酰-2-油酰-sn-甘油-3-乙基磷酸胆碱（EPC）对两性离子膜模型的亲和力，发现抑制剂肽与生物膜的结合主要由疏水相互作用而非静电相互作用驱动。西夫韦肽相对于恩夫韦肽效率的提高可能与其吸附在刚性脂质区域（如病毒包膜和脂筏）的能力有关，这导致融合位点处西夫韦肽浓度增加。
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