Peptidomimetics approaches for developing biologically active molecules

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Proteins and small natural peptides play a key role in many biological phenomena by interacting with other biomolecules, and often provide excellent therapeutic pathways. However, natural proteins and 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. Synthetic molecules that mimic natural peptides, but are conformationally and metabolically more stable, such as beta-peptides, are therefore viable alternatives as therapeutics. The folded structures of these unnatural peptide-mimics or peptidomimetics can provide enhanced interaction with the biological systems, just like the natural peptides with stable secondary structure facilitate some interactions better than others. The objective of the proposed research is to study structure-activity relationship among two new families of synthetic beta-peptides. These beta-peptides will be synthesized from easily accessible L-aspartic acid and beta-amino-L-alanine monomers. In this context, peptide and peptidomimetic analogs of several biologically active peptides such as class IIa bacteriocins and a short peptide sequence from SARS virus receptor protein, will be synthesized and the relationship of their conformation to activity will be studied. An alternate approach to the design of metabolically stable peptidomimetics is the use of a carrier system for the delivery of potent natural peptides, such as a bacterial system or liposomes. Peptide analogs of microcin J25 will be synthesized for delivery using a bacterial expression system.