Biomedical Engineering Reference
In-Depth Information
8 Peptides and Peptidomimetics
Minying Cai, Vinod V. Kulkarni, and Victor J. Hruby
CONTENTS
8.1 Introduction to Peptides and Peptidomimetics ................................................................... 123
8.2 General Features of Peptide Structure ................................................................................ 124
8.3 Design Considerations ........................................................................................................ 124
8.3.1 Ligand-Based Design............................................................................................. 125
8.3.1.1 Identifying Pharmacophore Elements.................................................... 126
8.3.1.2 Conformation of the Pharmacophore..................................................... 126
8.3.1.3 b-Turn Peptidomimetics and Other Peptide Mimetics........................... 131
8.3.1.4 Applying Computational and Biophysical Studies for Design............... 131
8.3.2 Design Based on the Biological Function.............................................................. 132
8.4 Modeling and Docking .......................................................................................................133
8.5 Conclusions ......................................................................................................................... 133
Further Readings............................................................................................................................ 133
8.1 INTRODUCTION TO PEPTIDES AND PEPTIDOMIMETICS
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 grow-
ing interest in the use of peptides as drugs for the treatment of diseases. The i eld 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 discontinu-
ous 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 struc-
tural, conformational, topographical, and dynamic properties of peptides that can be controlled
123
 
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