The first approach is shown in figure 3.1. This approach uses various techniques
(e.g., alanine scanning) to identify the smallest peptide segment with biological activity
within the overall peptide. This “minimal bioactive segment” may be cyclized or have
its stereochemistry altered in order to attain restriction of conformational freedom and
114 MEDICINAL CHEMISTRY
Figure 3.1 Peptidomimetic chemistry attempts to produce a non-peptidic drug to mimic a
bioactive peptide. In Step A, the smallest bioactive fragment of the larger peptide is identified; in
Step B, a process such as an alanine scan is used to identify which of the amino acids are impor-
tant for bioactivity; in Step C, individual amino acids have their configuration changed from the
naturally occurring L-configuration to the unnatural D-configuration (in an attempt to make
the peptide less “naturally peptidic”); in Step D, individual amino acids are replaced with atypical
unnaturalamino acids and amino acid mimics; in Step E the peptide is cyclized to constrain it con-
formationally; finally, in Step F, fragments of the cyclic peptide are replaced with bioisosteres in
an attempt to make a non-peptidic organic molecule.