Since the 1950s with the discovery of the peptide hormones and neurotransmitters, oxytocin and vasopressin, and the peptide antibiotics such as penicillin and valinomycin there has been a growing interest in the use of peptides as drugs for the treatment of diseases. The field is now extremely vast with thousands of papers published each year, with over 50 peptide- and peptidomimetic-based drugs, and with literally hundreds of other peptides in various phases of development as drugs. In addition, it is increasingly realized that the modulation and control of most biological processes, especially in more advanced forms of life such as multicellular animals, are controlled or modulated by peptide-protein, peptide-nucleic acid, peptide-lipid, protein-protein, protein-nucleic acid, and protein-lipid interactions (in the latter protein-X interactions, it is often a continuous or discontinuous polypeptide segment of the protein that is involved in the interaction, signaling, modulation, or other physiological effects). The interest on how to effectively utilize peptides and peptidomimetics to control their effects on health and disease has become a central theme of modern biology and medicine.
We have chosen to emphasize those aspects of peptide and peptidomimetic chemistry that are most important to know and to understand if one is to utilize bioactive peptides as the basis for drug design and discovery. For this purpose we have chosen peptide hormones and neurotransmitters as our major focus. These peptides are known to be critical molecules in virtually all bodily functions, in all aspects of human behavior, and in many aspects of disease—both peripheral diseases such as cardiovascular disease and diabetes, and in most diseases of the central nervous system (CNS) from anxiety and depression to sexual function, addiction, and obesity.
Therefore, in this chapter, we will examine the intrinsic properties of peptides, including structural, conformational, topographical, and dynamic properties of peptides that can be controlled and modified to obtain insights into the structural and conformational properties that can lead to peptidomimetics. In this regard, we should begin by carefully defining our terms. A "peptide" is a biopolymer made up of amide (peptide bond) linked a-amino acids. A "peptidomimetic" is a derivative of a peptide that possesses modifications of a common peptide structure including peptides containing 0- or y-amino acids; peptoid structures; amide bond replacements in their structure; side chain-modified structures such as 0-alkyl or aryl-substituted a-amino acids; unusual side chain cyclizations including lactam bridges, lactone bridges, alkane, or alkene bridges, and other side-chain-to-side-chain bridges; side-chain-to-backbone and backbone-to-backbone cyclizations. Nonpeptide peptidomimetics whose design is based on peptides will not be discussed here, nor will so-called peptide mimetics that are discovered as part of some screening processes of chemical libraries. In any case, these compounds often do not truly mimic the peptide structure related to its pharmacophore and often when examined carefully have different biological activity profiles.
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