Design, synthesis, and anti-inflammatory activity of analogs of tetrapeptide Phe-Glu-Leu-Leu

Inflammation is part of the defense mechanism of the organism, which provokes different signaling pathways. It is also related to several inflammatory mediators, such as cytokines and enzymes from the phosphodiesterase group, especially phosphodiesterase 4 (PDE4). On the other hand, peptides play diverse physiological roles as neurotransmitters, neuromodulators, hormones, and enzyme modulators. Taking these facts into account, the anti-inflammatory activity of several C-terminal amide analogs of tetrapeptide Phe-Glu-Leu-Leu was investigated using the carrageenan-induced paw edema model, and their inhibitory activity against PDE4 was evaluated. It was found that Val and Ile substitutions at positions 3 and 4 improved anti-inflammatory activity in vivo , with compounds BB3 and BB4 producing statistically significant reductions in carrageenan-induced edema at the 3 h time point, although these effects were not sustained at later observations. However, the same substitutions did not consistently enhance PDE4 inhibition. The parent compounds BB1 (C-terminal amide) and BB11 (C-terminal free acid) demonstrated the most balanced overall profile, combining moderate PDE4 inhibitory activity (49% and 58% inhibition at a concentration of 5 mM, respectively) with favorable in vivo anti-inflammatory properties. These findings highlight the complex relationship between peptide structure, PDE4 inhibition, and anti-inflammatory efficacy.