Peptidomimetics for Receptor Ligands—Discovery, Development, and Medical Perspectives

Abstract

Peptides, as neurotransmitters, neuromodulators. and hormones, influence a multitude of physiological processes by signal transduction mediated through receptors. In addition, during the last 20 years their role in the appearance or maintenance of various diseases could be unequivocally proven. Agents that can imitate or block the biological functions of bioactive peptides (agonists or antagonists, respectively) can be considered as aids for the investigation of peptidergic systems and also as therapeutic agents. The suitability of bioactive peptides as therapeutic agents was examined after preliminary pharmacological experiments. It was thereby shown that based on their pharmacological properties, for example degradation by peptidases or poor bioavailability, they could be employed as drugs in only a few cases. To solve this problem peptidomimetics, compounds that act as substitutes for peptides in their interaction with receptors, have been synthesized. In comparison with native peptides they show higher metabolic stability, better bioavailability, and longer duration of action. Peptidomimetics with antagonistic properties were also developed within the range of these investigations. As a result, new types of treatment and therapy for a series of diseases are possible. Although peptidomimetics have been developed largely by empirical methods (e.g. modification of native peptides, optimization of lead structures), methods for rational design based on investigations into the structure of peptide-peptide receptor complexes and studies of conformation energies, among others, are gradually being established.

Peptide blocking of IgE/receptor interaction: possibilities and pitfalls

“…Tliis will ideally be a totally nonpeptidic compound that mimics the key structural properties of the complementary partner of the interaction by virtue of having appropriate functional groups oriented for interaction with the receptor (75)(76)(77)(78). Examples of published drug discovery programs which have embraced hierarchic, structure-based approaches broadly similar to those indicated above include studies on the somatostatin-opioid (79) and cyclophilin-cyclosporin (80) interactions and tiiimics of streptavidin (81), RGD (72,82,83), and EPO (84, 85) binding motifs.…”

Synthesis of a bicyclic δ-amino acid as a constrained Gly-Asn dipeptide isostere

“…In this context, the area of peptidomimetics provides new dimensions to the field of molecular diversity and drug discovery (Giannis and Kolter, 1993;Gante, 1994;Adessi and Soto, 2002). In particular, the development of new leads for drug discovery has taken advantage of the use of unnatural amino acids in different fields of medicinal chemistry, for the development of peptidomimetics possessing high molecular diversity and the capability to generate high-ordered structures (Cole, 1994;Juaristi and Lopez-Ruiz, 1999;Trabocchi et al, 2005;Trabocchi et al, 2007).…”

The three‐dimensional solution structure of a constrained peptidomimetic in water and in chloroform observation of solvent induced hydrophobic cluster

“…To overcome this averaging, extensive effort has been devoted to the design of constrained peptides and peptide mimetics (peptidomimetics). A number of conformational studies of turns in peptides and peptidomimetics have been performed [1][2][3][4][5]. However, the critical role of the solvent environment and its effect on conformation cannot be neglected when *Corresponding authors.…”