Lipid bilayers play a central role in cells by serving as barriers for transport. In particular, they permit the passage of those molecules and ions that are necessary for maintaining the living state. At the same time, their hydrophobic core restricts the entry of many important classes of biologically-active agents that have therapeutic potential, especially ones that are strongly hydrophilic; e.g., oligonucleotides. Finding ways to improve the transport of hydrophilic molecules across lipid bilayers, in general, has proven to be one of the most formidable challenges facing medicinal chemists.
With this challenge in mind, we have introduced a unique class of amphiphilic molecules that interconvert between two different morphological states in response to changes in microenvironment. Such amphomorphic compounds mimic, in a sense, the structure and function of umbrellas by being able to cover an attached agent and shield it from an incompatible environment. Specifically, molecular umbrellas have been created, which consist of two or more facial amphiphiles that are covalently linked to a central scaffold. When immersed in a hydrocarbon environment, these compounds can adopt a shielded conformation in which the facially amphiphilic units not only mask their own hydrophilicity, but also that of an attached agent. When immersed in an aqueous environment these same molecules can expose their hydrophilic faces and the attached hydrophilic agent by favoring an exposed conformation. A stylized illustration of a molecular umbrella in an exposed and a shielded conformation is shown above, where the shaded and unshaded rectangles represent hydrophobic and hydrophilic faces, respectively. Current research in this area is focusing on (i) the design and synthesis of molecular umbrella conjugates that act as antifungal agents, (ii) the transport properties of these conjugates using model membranes, (iii) the cytotoxicity of these agents with respect to fungal and mammalian cells, and (iv) the efficacy of selected molecular umbrella conjugates in crossing the blood-brain barrier based on animal models.
This is a collaborative project with Professor John Perfect (Duke University School of Medicine) that offers a new therapeutic approach for the treatment of fungal meningitis. In a broader context, this program has the potnetial for creating a new paradigm for the transport of many other drugs into the central nervous system.