Biomedical Engineering Reference
In-Depth Information
6.2 DEFINITION AND CLASSIFICATION OF PEPTIDOMIMETICS
The standard approach to the generation of peptidomimetics is focused on knowledge
of the electronic and conformational features of the native peptide and its receptor or
active site of an enzyme. Thus, the development of peptidomimetics as compounds
possessing biological activity must take account of some basic principles [8],
including:
Replacement of the peptide backbone with a nonpeptide framework: If an amide
bond does not influence the biological activity, or amide bonds are not exposed
to the active site, the template may be designed to eliminate such peptide bonds.
Preservation of the side-chain functionalities involved in biological activity, as
they constitute the pharmacophore. In the development of second-generation
mimetics, several modifications should be taken into account so as to improve
the biological activity, including chain-length modification, introduction of con-
straints, cyclopeptide bond replacement with a covalent binding, and the intro-
duction of isosteric replacements [9].
Maintenance of flexibility in first-generation peptidomimetics: If a biological
activity is observed for a flexible mimetic, the introduction of elements of
rigidity to side chains is a rational approach to improving the preliminary
activity observed. This can be done by incorporating amino acids, which can
adopt only a very limited number of different conformations, or by introducing
cycles in the molecule.
Selection of proper targets based on a pharmacophore hypothesis; knowledge
of the structure-activity relationship or the three-dimensional structure of the
bioactive conformation is an important issue in achieving the best compound
rapidly without generating an enormous number of compounds with poor bio-
logical activity.
Peptidomimetics may be subdivided into three classes, depending on their struc-
tural and functional characteristics [10]:
1. Structural mimetics or type I mimetics. These compounds show the strict
analogy of a local topography with the native substrate, and they carry all the
functionalities responsible for interaction with an enzyme or a receptor in a
well-defined spatial orientation.
2. Functional mimetics or type II mimetics. In these molecules the analogy with
the native compound is based on interaction with the target receptor or enzyme,
without apparent structural analogies.
3. Structural-functional mimetics or type III mimetics. This class of pep-
tidomimetics is commonly represented by a scaffold having a structure different
from the substrate, in which all the functional groups necessary for biological
interactions are mounted in a well-defined spatial orientation.
A typical example of the third class of peptidomimetics is reported in the literature
for thyrotropin-releasing hormone (TRH) mimetics, which are based on a central
