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.

Public Health Relevance

This application addresses elucidation of mechanisms of peptide assembly into spherical nanoparticles and structure-based optimization of anti-cancer activity of chemokine receptor CXCR4 inhibitor peptide f22. PEGylated f22 peptide assembles into spherical nanoparticles, inhibits breast cancer growth, and prolongs survival in mouse breast cancer dissipation model. F22 self-assembly into nanoparticles may prevent peptide degradation in the blood stream and provide targeted delivery of f22 to CXCR4 expressing tumors due to the enhanced permeability and retention effect. The knowledge acquired as a result of the proposed research may be applied to the development of novel peptide pharmaceutical agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA135341-03
Application #
8212263
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Fu, Yali
Project Start
2010-02-04
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$316,002
Indirect Cost
$114,727
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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