Advances in Amino Acid Chemistry and Peptide Mimicry

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Peptides are natural biopolymers composed of chains of amino acids. Prominent examples serving as drugs include oxytocin, insulin, cyclosporin and salmon calcitonin, which are widely used in childbirth, diabetes, immunosuppression and osteoporosis, respectively. Research on the synthesis and science of peptides has experienced intense growth in both academic and industrial sectors, because of their remarkable versatility as building blocks and as tools for innovation in various fields. For example, the global market for peptide drugs is predicted to grow at an accelerated rate from US $14.1 billion in 2011 to US $25.4 billion in 2018, with currently, 60-70 approved peptide drugs, 100-200 more in clinical trials, and 400-600 more in pre-clinical studies. Paralleling interest in peptides for medical uses has been proportional growth in research featuring peptides in catalysis, materials science and nano-technology. Inherent in all peptide research are desires for insight into their active conformers and means to improve their stability and bioavailability. Although peptides evolved to be flexible and degradable for roles such as food and endogenous messengers in physiological systems, such properties are often drawbacks for programs desiring to harness them for specific tasks requiring longer durations of action. Our research program in peptide mimicry penetrates the heart of this predicament by providing tools for systematically studying structure-activity relationships to obtain insight about active conformers and means to improve their specificity and stability. Three classes of peptide mimic will be pursued: turns, loops and amino acid isosteres. Peptide turns are used in nature for various recognition events: e.g., peptide hormone – receptor, peptide antigen – antibody, and between the sites on protein surfaces and the enzymes, which can modify them by adding sugars or phosphates. Mimicry of turns has thus important impact in understanding natural conformations responsible for biological activity and to develop more drug-like molecules from peptide lead structures. Loops are involved in recognition events, which typically demand larger surface areas than turns: e.g., protein recognition by antibodies. We propose a lynchpin strategy to constrain peptide loops, which may be assembled later onto molecular scaffolds in order to mimic proteins that recognize discontinuous surface areas of larger molecules. Isosteres of amino acids are surrogates of these building blocks of peptides and proteins, which may constrain the backbone of these polymers as well as serve as mimics of the state of transition when peptide bonds are hydrolyzed by digestive enzymes and thereby inhibit the latter. All three of these targets have utility for preparing analogs of biologically active peptides to study and replicate the elements responsible for function. Employing these three motifs to study novel peptide targets with four different collaborators, our fundamental studies will be applied to make prototypes of drugs for treating AIDS, cancer and cardiovascular diseases, major causes of death in Canada. Studying the chemistry of these three motifs in such collaborations, my students are well trained in modern synthetic methods, spectroscopic techniques to explore the impact of constraint on peptide geometry and in communication with our biological counterpart to understand relationships between structure and activity. Finally, although focused primarily on using peptides in medicinal chemistry, my program benefits from broad scientific interests and aptitude for collaborative research to capitalize on opportunity impacting other fields: e.g., polymer science, photochromic devices and natural product synthesis.