ABSTRACT
The proper orientation of pharmacologically important side chains around a central core is fundamental to medicinal chemistry. Nature accomplishes this orientation in peptides and proteins by displaying amino acid side chains around the peptide backbone. Libraries of peptides are often used to identify the proper side chains and orientation for binding to a receptor or enzyme active site. However, peptides (amino acid oligomers) have significant pharmacological drawbacks that typically make them unsuitable as orally bioavailable drugs. A number of unnatural oligomers have been reported in recent years, many of which have been synthesized on a solid-phase or soluble polymer support. In their attempts to mimic the display of side chains by a normal peptide backbone, chemists have developed these various oligomers, while endeavoring to overcome some of the liabilities of peptides (i.e., susceptibility to proteolysis, poor bioavailability, etc.). Several examples of unnatural oligomers are shown in Figure 21, along with a natural peptide backbone for comparison [97-105]. This figure is not meant to represent an inclusive set, as several other unnatural oligomers (e.g., the peptide nucleic acids mentioned in the previous section) have also been synthesized.
