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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.
See this image and copyright information in PMC

References

    1. Dennis E.A., Norris P.C. Eicosanoid storm in infection and inflammation. Nat. Rev. Immunol. 2015;15:511–523. doi: 10.1038/nri3859. - DOI - PMC - PubMed
    1. Nakanishi M., Rosenberg D.W. Multifaceted roles of PGE2 in inflammation and cancer. Semin. Immunopathol. 2013;35:123–137. doi: 10.1007/s00281-012-0342-8. - DOI - PMC - PubMed
    1. Sterzel R.B., Schulze-Lohoff E., Marx M. Cytokines and mesangial cells. Kidney Int. Suppl. 1993;39:S26–S31. - PubMed
    1. Gomez-Guerrero C., Hernandez-Vargas P., Lopez-Franco O., Ortiz-Munoz G., Egido J. Mesangial cells and glomerular inflammation: From the pathogenesis to novel therapeutic approaches. Curr. Drug Targets Inflamm. Allergy. 2005;4:341–351. doi: 10.2174/1568010054022169. - DOI - PubMed
    1. Kokotou M.G., Limnios D., Nikolaou A., Psarra A., Kokotos G. Inhibitors of phospholipase A2 and their therapeutic potential: An update on patents (2012–2016) Expert Opin. Ther. Pat. 2017;27:217–225. doi: 10.1080/13543776.2017.1246540. - DOI - PubMed