Molecular Umbrellas as Membrane Transporters

描述（由申请人提供）：分子伞代表一类独特的两亲物，已证明其能够在不破坏膜完整性的情况下将某些亲水性肽转运穿过磷脂双层。最近，还发现分子伞能够（i）将16-mer寡核苷酸转运穿过富含胆固醇的磷脂双层，（ii）增加疏水性药物的水溶性和水解稳定性，并抑制HIV和HSV与哺乳动物细胞的结合。这项研究的具体目标建立在这些最新发现的基础上。特别是，这项研究旨在提供一个理解框架（即，发展基础科学），这将允许合理利用这些发现。具体而言，本研究的目标旨在（i）阐明分子伞的总长度、表面两亲性单元和连接的寡核苷酸之间的间距、其屏蔽能力、表面亲水性程度以及表面胍基的存在如何影响其转运寡核苷酸穿过富含胆固醇的磷脂双层的能力，（ii）测试产生具有高临界胶束浓度、高水解稳定性和高膜选择性的两性霉素B的分子伞缀合物的可行性，和（iii）确定过硫酸化分子伞的大小对双层转运和抗病毒活性的影响。该计划的长期目标是设计基于分子伞使用的药物递送的根本性新方法。 相关性：药物化学中的主要挑战之一是找到有效地将药物转运到细胞中的方法，以便它们能够在不破坏细胞膜完整性的情况下到达预期目标。特别是，细胞的外部“皮肤”已被证明是限制许多水溶性药物进入的重要屏障。这项研究的目的是通过设计能够携带药物穿过这些屏障的分子来找到解决这一问题的通用方法。这项研究有可能导致新的和更有效的药物，可用于治疗各种疾病;例如，癌症、艾滋病毒、疱疹病毒和真菌感染。

DESCRIPTION (provided by applicant): Molecular umbrellas represent a unique class of amphiphiles that has proven capable of transporting certain hydrophilic peptides across phospholipid bilayers without damaging the integrity of the membrane. Very recently, molecular umbrellas have also been found capable of (i) transporting a 16-mer oligonucleotide across cholesterol-rich phospholipid bilayers, (ii) increasing the water- solubility and hydrolytic stability of a hydrophobic drug, and inhibiting the binding of HIV and HSV to mammalian cells. The specific aims of this research build upon these latest findings. In particular, this research is intended to provide a framework of understanding (i.e., to develop the basic science) that will allow for the rational exploitation of these findings. Specifically, the goals of this research are aimed at (i) clarifying how the overall length of a molecular umbrella, the spacing between facially amphiphilic units and an attached oligonucleotide, its shielding capacity, the degree of facial hydrophilicity, and the presence of facial guanidinium group affect its ability to transport an oligonucleotide across cholesterol-rich phospholipid bilayers, (ii) testing the feasibility of creating molecular umbrella conjugates of Amphotericin B that exhibit high critical micelle concentrations, high hydrolytic stability and high membrane selectivity, and (iii) defining the consequences of the size of persulfated molecular umbrellas on bilayer transport and on antiviral activity. The long-term objective of this program is to devise fundamentally new approaches to drug delivery based the use of molecular umbrellas. RELEVANCE: One of the major challenges in medicinal chemistry is to find ways of transporting drugs, effectively, into cells so that they can reach their intended target without damaging the integrity of the membrane. In particular, the outer "skin" of cells has proven to be a significant barrier that has limited the access of many water-soluble drugs. This research is aimed at finding a general solution to this problem by designing molecules that can carry drugs across such barriers. This research has the potential for leading to new and more effective drugs that could be used to treat a wide range of diseases; e.g., cancer, HIV, Herpes virus and fungal infections.