The long-term goal of the program is to invent new materials that promote or inhibit the fusion of biological membranes. The work will bring practical as well as intellectual benefits to health and health science. From a practical perspective, the development of new fusion catalysts would be a welcome technological advance in the fields of hybridoma research, gene therapy and drug delivery; whereas, fusion inhibitors may be useful as novel therapeutic agents for a range of disease areas, especially opportunistic infection. There will be substantial intellectual contributions as the promoters and inhibitors are designed to test our current understanding of membrane fusion at the molecular level. Most of the early work will use model liposome systems. This is because biological membranes are complicated, heterogeneous matrices, and it is difficult to delineate the controlling molecular factors. However, there is good evidence that liposomes fuse by a similar mechanism, and that the knowledge gained form the model studies can be used to explain how fusion proteins work. Furthermore, a detailed understanding of liposome fusion is itself a clinically useful goal because liposomes are used as drug delivery vehicles. Currently, the stalk hypothesis is the most accepted, general mechanism for membrane fusion. However, it is hard to prove this mechanism because the transient fusion intermediates are difficult to observe and characterize. A close examination of the stalk mechanism suggests that molecules with specific topologies and polarities should be able to stabilize or destabilize the putative fusion intermediates and thus promote or inhibit fusion.
The specific aims of this application are: 1. Test the recently hypothesized, extended conformation mechanism for membrane fusion by evaluating the fusion inhibition ability of a series of conformationally restricted polar lipids. 2. Prepare and evaluate fusion promoters that are rationally designed to facilitate the stalk fusion mechanism. Two types of fusion promoters will be explored, (i) hydrophobic hexadecane dendrons that fill and stabilize the stalk interstitial voids, and (ii) spherical, ionic dendrimers that stabilize the highly curved surfaces of the stalk fusion intermediates. An effective promoter will be viewed as supporting evidence for the stalk mechanism, whereas negative results will require the model to be re-evaluated. 3. Prepare a series of dendrimer-steroid and dendrimer-liposome conjugates and evaluate if they have potential applications in gene therapy and drug delivery. 4. Use the accumulated data to formulate an improved molecular mechanism for biological membrane fusion.
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