Peptide Design Considerations

Abstract

Peptides have become an increasingly important class of molecules in biochemistry, medicinal chemistry, and physiology. Many naturally occurring, physiologically relevant peptides function as hormones, neurotransmitters, cytokines, and growth factors. Peptide analogs that possess agonist or antagonist activity are useful as tools to study the biochemistry, physiology, and pharmacology of these peptides, to characterize their receptor(s), and to study their biosynthesis, metabolism, and degradation. Radiolabeled analogs and analogs bearing affinity labels have been used for receptor characterization and isolation. Peptide substrates of proteases, kinases, phosphatases, and aminoacyl or glycosyl transferases are used to study enzyme kinetics, mechanism of action, and biochemical and physiological roles and to aid in the isolation of enzymes and in the design of inhibitors. Peptides are also used as synthetic antigens for the preparation of polyclonal or monoclonal antibodies targeted to specific sequences. Epitope mapping with synthetic peptides can be used to identify specific antigenic peptides for the preparation of synthetic vaccines, to determine protein sequence regions that are important for biological action, and to design small peptide mimetics of protein structure or function. A number of peptide hormones or analogs thereof, including arginine vasopressin, oxytocin, luteinizing hormone releasing hormone (LHRH), adrenocorticotropic hormone (ACTH), and calcitonin, have already found use as therapeutic agents, and many more are being investigated actively. Peptide-based inhibitors of proteolytic enzymes, such as angiotensin converting enzyme (ACE) and human immunodeficiency virus (HIV) protease, have widespread clinical use, and inhibitors of renin and elastase are also being investigated for therapeutic use. Finally, peptides designed to block the interaction of protein molecules by mimicking the combining site of one of the proteins, such as the fibrinogen receptor antagonists, show great therapeutic potential as well. With the development of solid-phase peptide synthesis by Bruce Merrifield (1963) and the optimization of supports, protecting groups, and coupling and deprotection chemistries by a large number of researchers, it has become possible to obtain useful amounts of peptides on a more or less routine basis.