Aspects of Peptidomimetics - Peptide and Protein Design for Biopharmaceutical Applications - page 50

A further step includes peptide bond modifications, C a substitutions and
chain extensions, resulting in derivatives with partial peptide character, or
pseudopeptides . This combined knowledge, supplemented by conforma-
tional studies using NMR spectroscopy, X-ray diffraction, CD and mole-
cular modelling, is used to generate a 3D pharmacophore model, which then
allows the de novo design of a peptidomimetic. Peptide pharmacophoric
groups can be displayed with a defined 3D orientation on a variety of
scaffolds, many of which are small heterocycles, including 'privileged tem-
plates'. Various definitions of peptidomimetics have been given in the
literature [4]. Some investigators use the term 'peptide mimetic' to refer to
pseudopeptides and even modified peptides. Moore uses a strict definition of
a peptide mimetic as a molecule that no longer contains peptide bonds [5]. A
definition given by V. Hruby describes a peptidomimetic as a designed
compound whose pharmacophoric structural elements mimic a peptide's
binding element in 3D space, mimicing the binding and agonist or antago-
nist activity of a natural peptide ligand [2]. In parallel to this rational design,
many compounds acting at peptide receptors as agonists or antagonists have
been discovered through random screening strategies, followed by classical
medicinal chemistry optimization. Although some of these do not bind to
the peptide receptor in the same way as the native peptide does [6], most
authors refer to them as peptidomimetics. Peptidomimetics have been classi-
fied as type I, II or III [6]. Type I mimetics are backbone-modified peptides.
Type II mimetics are small nonpeptide molecules that bind to peptide recep-
tors, and were mostly discovered by screening. Those designed mimetics
possessing novel templates on which the pharmacophoric groups are dis-
played to generate a topographical mimetic belong to type III [6].
Oligomeric compounds such as oligoureas and oligocarbamates have also
been termed peptidomimetics. Other examples include b-andg-peptides,
which adopt well-defined structures such as helices or sheets, and are there-
fore called 'foldamers'.
In this chapter, some of the aspects of the chemistry and applications
of modified peptides, pseudopeptides and peptidomimetics will be
discussed.

3.2 MODIFIED PEPTIDES

When peptide chemists are faced with a new bioactive peptide
sequence, the traditional approach to obtain structure-activity
data generally involves the use of N- and C-terminal truncations,