Biomedical Engineering Reference
In-Depth Information
of their conformation on the environment are relevant issues that make it difficult to
use such entities as templates for drug discovery.
In addition to all these limitations, biomedical research is constantly oriented
toward the development of new therapeutics based on peptides and proteins, by
introducing both structural and functional specific modifications and maintaining the
features responsible for the biological activity. These requirements are all matched in
the development of
peptidomimetics
[2-4]. In this approach, peptides and proteins are
considered as leads for the discovery of other classes of compounds. Peptidomimet-
ics play a prominent role as candidate compounds to induce phenotypic effects on
biological systems. In fact, side-chain recognition dominates the biological inter-
actions of almost all cellular processes; thus, peptidomimetics, developed initially
for their property of preventing degradation and improving oral bioavailability of
peptide-based drugs, have been envisaged as a tool for perturbing such interactions
and identifying protein functions. Small peptide-based agents have attracted wide
interest as anticancer and anti-infective agents, and there is a continuous need to
develop new high-affinity and high-specificity peptidomimetic or small-molecule
ligands in such widespread pathologies. Success in this area depends on the ability
to create novel complex molecular structures of peptidomimetic nature as tools for
probing protein-protein interactions.
A peptidomimetic compound may be defined as a molecule having a secondary
structure, besides other structural features similar to the parent peptide, such that
it binds to enzymes or receptors with higher affinity than the starting peptide. As
an overall result, the native peptide effects are inhibited (antagonist) or increased
(agonist). Apart from being much more selective and efficient than native peptides,
thus resulting in fewer side effects, peptidomimetics show greater oral bioavailability,
and biological activity is prolonged due to lowered enzymatic degradation [5,6].
The generation of peptidomimetic combinatorial libraries was reported initially
as modified peptides, taking advantage of the chemical diversity of the amino acids
and the sequence diversity. As an example, Dooley and Houghten described the gen-
eration of a wide range of combinatorial libraries, from peptides to low-molecular-
weight heterocyclic compounds, which have been screened successfully in assays
specific for opioid receptors, thus enabling the identification of new ligands for these
receptors [7]. During the past decade, the combinatorial concept has evolved to
diversity-oriented synthesis (DOS) in view of expanding the chemical diversity of
the central scaffold, as well as exploiting the appendage diversity on a fixed cyclic
chemical entity, which has been the most popular approach in classic combinato-
rial libraries. Very recently, several reports on DOS chemical methods encompass-
ing peptidomimetics and amino acid-derived scaffolds appeared in the literature,
possibly opening a perspective on expansion of the chemical diversity around the
peptidomimetic concept, in an effort to address “undruggable” protein-protein inter-
actions that have been identified as potential therapeutic targets for relevant diseases.
Accordingly, selected contributions addressing the generation of peptidomimetic and
amino acid-derived scaffolds following a DOS approach are presented in this chapter,
with the aim of giving a perspective view of what may be a promising way to merge
two powerful concepts to achieve brand new privileged structure carriers of high
chemical diversity.
