Design of Therapeutic Peptide-Based Nanoparticles

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DESCRIPTION (provided by applicant): With increasing investment into pharmaceutical industry there is a paradoxical decline in the number of new medicines on the market. One of the reasons for this phenomenon is the focus of pharmaceutical companies on small molecules for development of therapeutic agents. Although they are potent inhibitors of target proteins, small molecules are known for their low specificity. Larger and more complex molecules, such as peptides, provide more specific target recognition. However, peptides are unstable and require design of cellular delivery mechanisms. Utilization of structural plasticity of peptide molecules in biological solvents is a novel approach to solve the problems with peptide pharmaceutical agents. In aqueous solutions certain peptides exhibit a distinct beta-hairpin conformation that allows them to assemble into spherical nanostructures. Nanostructures encounter a hydrophobic environment of the plasma membrane, disassemble, insert into the membrane, change their conformation, and inhibit target proteins. I hypothesize that by studying the peptide assembly mechanism into nanoparticles it is possible to formulate a set of requirements for the design of peptides capable to form nanoparticles. The long term goal is to define the requirements for intermolecular interactions between peptides allowing assembly into nanoparticles. Understanding the mechanism of peptide structure transitions will enable development of novel therapeutic nanoparticles capable of performing an encoded sequence of tasks. I shall address the requirements for the design of such peptides by studying the structure of the monomeric peptides, the mechanism of nanoparticle assembly, and the structural changes in the lipid environment. I propose the following specific aims: (1) Determine the structural requirements for the monomeric peptide that allow assembly into nanoparticles using nuclear magnetic resonance (NMR) techniques; (2) Identify the intermolecular interactions responsible for peptide assembly into nanoparticles using NMR, electron microscopy, and dynamic light-scattering; (3) Analyze structural changes that the peptide molecules undergo in the lipid environment by NMR.