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. 2018 Jan 13;23(1):158.
doi: 10.3390/molecules23010158.

Small Peptides Able to Suppress Prostaglandin E₂ Generation in Renal Mesangial Cells

Sofia Vasilakaki  1 , Oleksandr Pastukhov  2 , Thomas Mavromoustakos  3 , Andrea Huwiler  4 , George Kokotos  5
Affiliations

Small Peptides Able to Suppress Prostaglandin E₂ Generation in Renal Mesangial Cells

Sofia Vasilakaki et al. Molecules. .

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.

Keywords: inhibitors; mesangial cells; peptides; prostaglandin E2; secreted phospholipase A2.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Inhibitors of secreted PLA2 able to suppress the formation of PGE2 in mesangial cells.
Figure 2
Figure 2
The design of new inhibitors was based on alterations of Groups A and B of GK115 structure. The table describes the alterations of Groups A and B and the corresponded generated compounds in brackets.
Scheme 1
Scheme 1
Reagents and conditions: a. H-Nle-Gly-OMe, WSCI·HCl, HOBt, Et3N, CH2Cl2; b. 1 N aq NaOH, MeOH.
Scheme 2
Scheme 2
Reagents and conditions: a. WSCI·HCl, HOBt, Et3N, CH2Cl2; b. 1 N aq NaOH, MeOH.
Scheme 3
Scheme 3
Reagents and conditions: a. H-Gly-Nle-OMe, WSCI·HCl, HOBt, Et3N, CH2Cl2; b. 1 N aq NaOH, MeOH; c. H-Gly-OtBu, WSCI·HCl, HOBt, Et3N, CH2Cl2; d. CF3COOH, CH2Cl2.
Figure 3
Figure 3
Effect of compounds 7, 11, 14a, 14b and 16a on IL-1β/Fk-stimulated PGE2 formation in mesangial cells. Data are presented as % of maximal IL-1β/Fk stimulation and are means ± S.D. (n = 3). ** p < 0.01, *** p < 0.001 considered statistical significant when compared to the IL-1β/Fk samples. Basal PGE2 concentration was at 7.9 ± 5.3 pg/100 μL supernatant; the maximal IL-1β/Fk-stimulated PGE2 concentration was at 685 ± 81 pg/100 μL supernatant.
Figure 4
Figure 4
Binding pose prediction of GK115 in the active site of sPLA2 GIIA (red: oxygen atoms, blue: nitrogen atoms, green: calcium atom).
Figure 5
Figure 5
Binding pose prediction of 11 in the active site of sPLA2 GIIA (red: oxygen atoms, blue: nitrogen atoms, green: calcium atom).
Figure 6
Figure 6
Root-mean-square deviation (RMSD) values of inhibitors 11 (green) and GK115 (orange) in the active site of sPLA2 GIIA during the MD simulation time.
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