WHO has reported that antibiotic resistance is the third major cause of human death all over the globe. Recent study, has focused on the development of new antibacterial resistance drugs. Herein, we tried to synthesis a series of polymers that can mimic the HDPs. HDPs can target the bacterial cell membrane and they have less chances to develop bacterial resistance. We synthesized the amphiphilic polycarbonates that are highly selective to Gram-positive bacteria, including multidrug resistant pathogens. The membrane disruption activity of these polymers was proved by fluorescence and TEM studies and the drug resistance study showed that the polymers don’t develop bacterial resistance. In order to further design the molecules that can target a broad spectrum of bacteria, we have designed a series of lipidated dendrimers that can target the Gram-positive and Gram-negative bacteria. These dendrimers mimic the HDPs and target the bacterial cell membrane. Dendrimers are reported to inhibit the formation of bacterial biofilm which makes them promising for their future development of antibiotic agents. Apart from the synthesis of polymers and dendrimers as antibacterial agents, we have designed a series of small molecular antibacterial agents that are based on the acylated reduced amide scaffold and small dimeric cyclic guanidine derivatives. These molecules display good potency against a panel of multidrug-resistant Gram-positive and Gram-negative bacterial strains. Meanwhile, they also effectively inhibit the biofilm formation. Mechanistic studies suggest that these compounds kill bacteria by compromising bacterial membranes, a mechanism analogous to that of host-defense peptides (HDPs). Lastly, we also demonstrate that these molecules have excellent in vivo activity against MRSA in a rat model. This class of compounds could lead to an appealing class of antibiotic agents combating drug-resistant bacterial strains.

Peptidomimetics can mimic hierarchical structures of peptides and proteins. Thus, they are extensively studied for therapeutic applications. To break the limitation of backbones and frameworks and expand the peptidomimetics family, a new class of peptidomimetics - “γ-AApeptides” was developed. Design of γ-AApeptides is based on the chiral peptide nucleic acids (PNAs) backbone. The World Health Organization estimates that one -third of all deaths in the world are on account of infectious diseases. AMPs are important because of their high activity against broad spectrum microbes, less susceptible to grow resistance and selectivity in binding to bacterial cells over human cells. γ-AApeptides as a new class of peptidomimetics have increased stability and enhanced chemical diversity. We have developed polymyxin mimic cyclic peptides, small linear molecules and hydantoin derivatives as potent antibiotic agents with γ-AApeptides. They have good bioactivity and selectivity. Combinatorial library is key technology for accelerating the discovery of novel therapeutic agents. One-bead-two-compound γ-AApeptides-based library was developed and screened against SMYD2 protein which is essential for tumor growing.

Alzheimer's diseases(AD) has been discovered and under research for more than 70 years, However there is no cure for these progressive and devastating diseases. Based on the following hypothsis: Aß metabolite problem/over production result in the accumulation, and lead to aggregation is the cause of Alzheimer’s disease. AApeptide and Melatonin derivatives can bind to Aß and block the aggregation of β amyloid monomers, decrease the toxicity of Aß to neurons and slow the progressive of Alzheimer’s diseases. In addition, AApeptide which mimic transmembrane peptide Tat will have similar transmembrane function. We have set up our goals as follows: 1) Using newly discovered peptidomimetics, AApeptides. We moved on to research to discover their potential of transmembrane activity and anti-Alzheimer's acitiviy. 2) In Addition, studies of small molecule melatonin derivatives were also progressed. Methods include in this research includes bioorganic synthesis, identification of spectroscopy and relative assays targeting on biological efficiency of Anti-Alzheimer’s diseases. The details of which will be described in Chapters. In conclusions, two sets of transmembrane peptidomimetics for drug transportation has been successfully evaluated and potential of AA peptide small molecules, melatonin derivativesare also evaluated. These works have gained good progress in research between AApeptide and Alzheimer’s Diseases. These works also established basis of research in developing peptidomimimetics as potential pharmacies against Alzheimer’s diseases.

Proteins can be described as the “machineries” responsible for almost all tasks in the levels of organizational complexity in multi-cellular organisms namely: the cells, tissues, organs and systems. Any disorder in the function of a protein at any of these levels could result in disease, and a study of protein function is critical to understanding the pathological features of the disease at the molecular level. A quick glance at these abundantly present proteins reveals two striking features: large diversity of biological function, and the variations in structural complexity, which varies from simple random coils, to turns and helices, and on to structured assemblies of turns, helices and sheets. Over the past few years, more research efforts have been channeled to the application of synthetic research to protein dynamics, most especially in disease conditions. This provides insight into the design and development of chemical tools capable of modulating protein functions .Some of such tools include small molecules, peptides and peptidomimetics. In this work, we have described the application of these tools to three (3) different disease systems topping the list of incurable diseases: HIV, Diabetes, and Cancer. We have designed and developed chemical probes to facilitate a better understanding of major “culprit” proteins underlying the pathological conditions associated with these diseases. Our designed chemical probes were capable of modulating protein functions by producing the desired effects: inhibition of protein-protein interactions.

Peptidomimetics are synthetic foldamers that expected more resistant to proteolytic degradation and enormous chemodiversity when compared with peptides. To date, the functional peptidomimetics such as β-peptides, peptoids, oligoureas, etc have been developed in many science fields. In order to explore the unnatural foldameric architectures, it’s necessary to discover the novel frameworks and molecular scaffolds. γ-AApeptides were reported to be a new class of peptidomimetics that showed its potential applications in drug discovery and chemical biology. However, a wide function and property of γ-AApeptides need to be further explored. To expand the potential application of γ-AApeptides in biochemistry, I have been focusing on the development of bioactive peptidomimetics, such as exploring the antibacterial activity of helical 1:1 α-sulfono-γ-AA heterogeneous peptides, developing the helical peptidomimetic as the inhibitor of the protein Ras_Raf interaction, identifying the protein/peptide ligands by the novel one-bead-two compound macrocyclic γ-AApeptide screening library, and elucidating the de novo dragon-boat-shaped synthetic foldamers.

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.