'Molecular Umbrellas as Membrane Transporters'

本研究的总体目标是更深入地了解分子伞在脂质双分子层上运输极性分子的机制，明确分子伞辅助双分子层运输的范围，并开发可切割的分子伞偶联物，以期开发前药。该项目的长期目标是开发分子伞作为生物活性药物的膜转运体，用于口服递送、血脑屏障递送和基因治疗。本筹资期的具体目标包括：(1)阐明分子伞-谷胱甘肽偶联物与磷脂膜之间的相互作用；(2)表征分子伞-谷胱甘肽偶联物的运输特性；(3)确定胆固醇对分子伞-肽偶联物双层运输特性的影响；(4)确定面部亲水性对膜运输的影响；(5)检测分子伞-寡丝氨酸偶联物的“针线”特性。(6)测试分子伞-寡核苷酸偶联物的“针线”特性；(7)合成分子伞偶联物，可以释放自由形态的生物活性肽。

The overall objectives of this research are to gain a deeper understanding of the mechanism by which molecular umbrellas transport polar molecules across lipid bilayers, to define the scope of molecular umbrella-assisted bilayer transport, and to develop cleavable molecular umbrella conjugates with a view towards the development of prodrugs. The long-term goal of this program is to develop molecular umbrellas as membrane transporters of biologically-active agents for oral delivery, for delivery across the blood-brain barrier, and for gene therapy. The specific aims for the current funding period include: (1) clarifying the interactions between molecular umbrella- glutathione conjugates and phospholipid membranes, (2) characterizing the transport properties of molecular umbrella- glutathione conjugates, (3) defining the influence of cholesterol on the bilayer transport properties of a molecular umbrella- peptide conjugate, (4) defining the influence of facial hydrophilicity on membrane transport, (5) testing for "needle and thread" properties of molecular umbrella-oligoserine conjugates, (6) testing for "needle and thread" properties of a molecular umbrella-oligonucleotide conjugate, and (7) synthesizing molecular umbrella conjugates that can release biologically- active peptides in their free form.