Peptidomimetics are synthetic oligomers that resemble the activities of peptides. Their advantages over peptides include high stability towards proteolysis and enormous chemical diversity. Over the past two decades, there have been extensive efforts to develop peptide mimics, such as beta-peptides, peptoids, D-peptides, etc. The research on peptidomimetics have led to many important applications in both medicinal and material science. In order to explore new functions, the discovery of peptidomimetics with novel frameworks is essential. We reported the synthesis and evaluation of a new class of peptidomimetics, termed as gamma-AApeptides. Previous studies of gamma-AApeptides have revealed that gamma-AApeptides are highly resistant to proteolysis, and are highly amendable to chemical diversification. However, new biological activities and folding properties of gamma-AApeptides still need to be explored. In order to expand the potential of gamma-AApeptides in chemical biology and medicinal chemistry, I have been focusing on the development of new methods to synthesize linear and cyclic gamma-AApeptides, development of one-bead-one-compound (OBOC) gamma-AApeptide libraries for the discovery of inhibitors against beta-amyloid aggregation, exploring new helical foldamers for the rational design of protein-protein interaction (PPI) inhibitors, and studying cyclic gamma-AApeptides for antimicrobial development.

There has been increasing concern regarding the emergence of multi-drug resistant pathogens. The resistance develops when pathogens, especially bacteria, are frequently exposed to conventional antibiotics, as they are heavily used in both human and livestock. This is due to the high target specificity of conventional antibiotics, which places pathogens in high selective pressures and eventually results in drug resistant by mutations. To address this issue, global actions and cooperation are needed. At the same time, new technologies and strategies need to be developed. Host defense peptides (HDPs) are widely found in the innate immune system. They show both direct antimicrobial properties and immunomodulatory activities. The multifaceted functions of HPDs make them less likely to promote antimicrobial resistance. Thus, they are promising as new therapeutics to treat multi-drug resistant infections. In fact, several drug candidates derived from HDPs have entered the clinical trial, but none of them got into the clinic. This is due to several challenges associated with HDPs, such as low in vivo stability, high cost of manufacturing, and toxicity to mammalian cells. In this dissertation, we explored the ability of a new type of unnatural scaffolds (γ-AApeptides) to mimic the functions of HDPs, including both broad spectrum antimicrobial properties and immunomodulatory activities. Furthermore, the efforts to identify simpler and more drug like γ-AApeptide based antimicrobial agents were also discussed. The findings in this dissertation may lead to the development of potential drug candidates to treat multi-drug resistant infections.