'Molecular Umbrellas as Membrane Transporters'

这项研究的总体目标是更深入地了解分子伞通过脂质双层转运极性分子的机制，确定分子伞辅助双层转运的范围，并开发可切割的分子伞结合物，以期开发前药。该计划的长期目标是开发分子伞作为生物活性物质的膜转运体，用于口服给药、跨血脑屏障给药和基因治疗。目前资助期的具体目标包括：(1)澄清分子伞-谷胱甘肽结合物与磷脂膜之间的相互作用，(2)表征分子伞-谷胱甘肽结合物的传输特性，(3)确定胆固醇对分子伞-肽结合物双层传输特性的影响，(4)确定表面亲水性对膜传输的影响，(5)测试伞状低聚丝氨酸分子结合物的“针线”性质，(6)测试分子伞-寡核苷酸结合物的“针线”性质，以及(7)合成能够以游离态释放生物活性多肽的分子伞结合物。

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.