Isopeptide bonds in chemotactic tripeptides. Synthesis and activity of lysine‐containing fMLF analogs

Abstract

In order to explore the properties of chemotactic N-formylpeptides containing isopeptide bonds within their backbones, a group of lysine-containing analogs of the prototypical chemotactic tripeptide N-formylmethionyl-leucyl-phenylalanine (fMLF) was synthesized. The new analogs were designed by adding to the HCO-Met or Boc-Met residue a dipeptide fragment made up of Lys and Phe residues joined through Lys N alpha or N epsilon bonds, in all possible combinations. Thus, the following six pairs of tripeptides were synthesized and examined for their bioactivity: RCO-Met-Lys(Z)-Phe-OMe (2a, b), RCO-Met-Lys(Z-Phe)-OMe (3a, b), Z-Lys(RCO-Met)-Phe-OMe (4a, b), Z-Phe-Lys(RCO-Met)-OMe (5a, b), RCO-Met-Phe-Lys(Z)-OMe (6a, b) and Z-Lys(RCO-Met-Phe)-OMe (7a, b), with R=OC(CH3)(3 )and R=H for compounds a and b, respectively. All the new models were characterized fully and their activity (chemotaxis, superoxide anion production and lysozyme release) on human neutrophils determined as agonists (compounds b) and antagonists (compounds a). All N-formyl derivatives 2b-7b are less potent than fMLF-OMe as chemoattractants, but compound 7b exhibits selective activity as superoxide anion producer. Derivatives 2a-7a do not show antagonistic activity towards fMLF induced chemotaxis and O(2)(-) production, however, all these compounds except 4a antagonize lysozyme release by 60%.

The cis-4-Amino-l-proline Residue as a Scaffold for the Synthesis of Cyclic and Linear Endomorphin-2 Analogues

“…In order to study structure–activity relationships and develop potent and selective analgesics, a great number of opioid peptide analogues have been synthesized and evaluated in the past decade. Native opioid peptides show poor bioavailability mainly due to the inability to penetrate the blood–brain barrier , and to the rapid degradation by peptidases such as aminopeptidases and dipeptidyl peptidase IV. − To overcome these limitations, different strategies have been developed and exhaustively reviewed. − Results from these studies suggest that the stabilization of folded structures may enhance endomorphin activity and underscore at the same time the relevant role that the spatial orientation of the three aromatic side chains may play. ,− In light of these observations and taking into account the intrinsic limitations of peptides as therapeutic agents, the synthesis of cyclic analogues appears particularly appealing. Although the adopted synthetic strategies may greatly differ, the most common methods are based on the introduction of bivalent amino acids so as to close lactam or disulfide bridges ,− or, more recently, on the adoption of ring closing metathesis …”

Synthesis and biological evaluation of new active For‐Met‐Leu‐Phe‐OMe analogues containing para‐substituted Phe residues

“…The different behavior can be rationalized on the basis of the existence of at least two different states and/or with different subtypes of FPRs . Low doses of a full agonist (or a ‘pure’ chemoattractant) are required to interact with a high‐affinity receptor subtype, which activates the transduction pathway responsible for chemotactic response, whereas an increase in agonist concentration allows binding with the low‐affinity subtype, able to activate the transduction pathways responsible for O 2 − production and lysozyme release . As a consequence, a peptide selective for killing mechanisms, which preferentially interacts with the low‐affinity subtypes, is efficient in effectively displacing the full agonist [ 3 H]‐fMLF only at high concentration.…”

Conformational investigations on analogs of inflammation response inducing chemotactic tripeptide fMLP

“…The retroisomer of fMLP, i.e., CHO–Phe–Leu–Met–NH 2 and its D analogs were found to be 100 to 10,000 times less active 74. Many other formyl peptides were also examined recently, for biological activities;75–95…”

“…To probe the structural requirement, these groups were mutated with residues having different steric, charge, and hydrophobic groups, and constraints were introduced to achieve the desired conformation. A large number of analogs of fMLP have been designed and synthesized, examined for their biological activities, and quite a few have also been studied for their conformation using X‐ray crystallography and NMR techniques 2, 9–22, 52–95. Results of conformational and activity studies on these peptides are summarized in Table V.…”