Abstract
Peptide drug discovery may play a key role in the identification of novel medicinal agents. Here, we present the development of novel small peptides able to suppress the production of PGE2 in mesangial cells. The new compounds were generated by structural alterations applied on GK115, a novel inhibitor of secreted phospholipase A2, which has been previously shown to reduce PGE2 synthesis in rat renal mesangial cells. Among the synthesized compounds, the tripeptide derivative 11 exhibited a nice dose-dependent suppression of PGE2 production, similar to that observed for GK115.
Highlights
Prostaglandin E2 (PGE2 ) is one of the most important lipid mediators [1] playing a pivotal role in inflammatory diseases [2] including glomerulonephritis
The biosynthesis of PGE2 is initiated by the action of phospholipases A2 (PLA2 ), which cleave the sn-2 ester bond of membrane glycerophospholipids to release arachidonic acid [5,6]
Arachidonic acid is converted to PGH2 and the terminal step of PGE2 generation is catalyzed by microsomal prostaglandin synthase-1 [7]
Summary
Prostaglandin E2 (PGE2 ) is one of the most important lipid mediators [1] playing a pivotal role in inflammatory diseases [2] including glomerulonephritis. Glomerulonephritis is initiated by the invasion of activated immune cells into the renal glomerulus and the release of pro-inflammatory cytokines such as TNFα and interleukin (IL) 1β to activate the local resident mesangial cells [3,4]. This activation includes three main responses, i.e., increased proliferation, increased matrix production, and increased inflammatory mediator production, which are all hallmarks of glomerulonephritis, resulting in glomerulosclerosis and renal failure [4]. Four types of PLA2 [6] are expressed at mesangial cells: cytosolic (cPLA2 )
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