Molecular Umbrellas as Membrane Transporters

描述(申请人提供)：分子伞是一种独特的两亲性化合物，已被证明能够在不破坏膜完整性的情况下通过磷脂双层传输某些亲水性多肽。最近，分子伞也被发现能够(I)通过富含胆固醇的磷脂双层运送16聚体寡核苷酸，(Ii)增加疏水药物的水溶性和水解性稳定性，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，这项研究的目的是提供一个理解框架(即发展基础科学)，以便合理利用这些发现。具体地说，这项研究的目标是：(I)澄清分子伞的总长度、面部两亲性单元与附着的寡核苷酸之间的间距、其屏蔽能力、面部亲水性程度以及面部胍基的存在如何影响其通过富含胆固醇的磷脂双层膜传输寡核苷酸的能力；(Ii)测试创建具有高临界胶束浓度、高水解性和高膜选择性的两性霉素B分子伞结合物的可行性；以及(Iii)确定过硫化分子伞的大小对双层传输和抗病毒活性的影响。该计划的长期目标是从根本上设计基于分子伞的药物输送的新方法。 相关性：药物化学的主要挑战之一是寻找有效地将药物输送到细胞内的方法，以便它们能够在不损害膜完整性的情况下到达预期的目标。特别是，细胞的外层“皮肤”已被证明是一个重要的障碍，限制了许多水溶性药物的获取。这项研究的目的是通过设计能够携带药物跨越这些障碍的分子来找到这个问题的一般解决方案。这项研究有可能导致新的、更有效的药物，可用于治疗多种疾病，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.