Functions and properties of native peptides vary from highly specific antibiotics or cytotoxic antitumor drugs, to hormones, neurotransmitters, immunomodulators, etc. Despite their potential utility as therapeutic agents, there are problems connected with the use of natural peptides, due to the low stability against proteolysis, resulting in a short duration of in vivo activity, and in a low bioavailability. One way to overcome these disadvantages is the use of modified peptides, the so called peptidomimetics. Overall, the less peptide character in a drug candidate, the more stable it is towards protease cleavage. A huge number of non-peptidic scaffolds have been reported in the literature; nevertheless, several cases have failed to reproduce the activity of the precursor peptide when the scaffold itself contains relevant pharmacophore elements. Therefore, quasi-peptides still maintain their appeal for applications in medicinal chemistry. For the large number of different unnatural amino acids and peptidomimetics, the overview cannot be all-inclusive. This review focuses on modified peptides in which the peptide character is still preponderant, with particular emphasis on the chemical methodologies utilized to introduce the modifications.

In this paper we describe the synthesis and affinity toward the mu-opioid receptor of some tetrapeptides obtained from endomorphin-1, H-Tyr-Pro-Trp-Phe-NH(2) (1), by substituting each amino acid in turn with its homologue. The ability to bind mu-opioid receptors depends on the beta-amino acid, and in particular 4, which contains beta-L-Pro, has a K(I) in the nanomolar range. The peptides 4 and 5 are significantly more resistant to enzymatic hydrolysis than 1. The same compounds, as well as the mu-opioid receptor agonist DAMGO, produced a concentration-dependent inhibition of forskolin-stimulated cyclic AMP formation, thus behaving as mu-opioid agonists. These features suggest that this novel class of endomorphin-1 analogues may represent suitable candidates for the in vivo investigation as potential mu-opioid receptor agonists.

Despite the fact that they have been used for a century to treat several kinds of diseases, peptides and short proteins are now considered the new generation of biologically active tools. Indeed, recent findings suggest a wide range of novel applications in medicine, biotechnology, and surgery. The efficacy of native peptides has been greatly enhanced by introducing structural modifications in the original sequences, giving rise to the class of peptidomimetics. This review gives an overview of both classical applications and promising new categories of biologically active peptides and analogs. Besides the new entries in well known peptide families, such as antibiotic macrocyclic peptides, integrin inhibitors, as well as immunoactive, anticancer, neuromodulator, opioid, and hormone peptides, a number of novel applications have been recently reported. Outstanding examples include peptide-derived semi-synthetic vaccines, drug delivery systems, radiolabeled peptides, self-assembling peptides, which can serve as biomaterials in tissue engineering for creating cartilage, blood vessels, and other tissues, or as substrates for neurite outgrowth and synapse formation, immobilized peptides, and proteins. Finally, peptide-based biomaterials can find applications in bio-nanotechnology for bio-microchips, peptide nanorods and nanotubes, bio-sensors, bio-electronic devices, and peptide-metal wires.

No abstract

No abstract