Investigation of peptides and peptidomimetics for developing bioactive molecules

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Peptides, or small fragments of proteins, have opened up immense possibilities for development of highly sensitive molecular and biological diagnostics, sensors with specific interaction and binding with numerous biomolecules, potential drugs, inhibitors, and food preservatives. However, natural alpha-peptides are frequently susceptible to proteolysis and metabolism, where they can be "consumed" or "broken down" by other biological entities before they reach their targets in a biologically active environment. Synthetic molecules that mimic natural peptides, but are conformationally and metabolically more stable, such as beta-peptides, are viable alternatives to natural peptides. These unnatural peptide-mimics or peptidomimetics can provide enhanced interaction with their target biological systems. The objectives of the proposed research are: a) design and synthesis of metabolically stable and biologically active peptidomimetics; and b) development of new methods to study peptide interactions in a variety of in vitro systems of biological, analytical, and environmental relevance. We will use automated (robotic) solid phase synthesis to design peptide arrays on cellulose membranes. Both alpha and beta peptide libraries will be synthesized from rational combinations of amino acids. Three scenarios of fundamental importance in peptide interactions or peptide binding will be studied. First, antibacterial peptide analogues will be designed, synthesized, and tested to mimic class IIa and IIb bacteriocins (which are potent antimicrobial peptides). Second, a model peptide based on a SARS virus receptor protein will be developed and tested as an embodiment of protein-protein interaction inhibitor. Third, a peptide array for identifying specific interactions with a Hepatitis C virus envelope protein will be developed to identify the most potent entry inhibitor. These three studies will provide a fundamental perspective of rational peptide design and synthesis for targeted applications. It is expected that this research will provide a broad-based platform for future development of peptide arrays as a viable tool for preparation of novel scaffolds for high-throughput studies of biological interactions.