Proceedings book download - 5Z.com

Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Structural Aspects and Biological Evaluation of New MannoseDerived Immunomodulating AdamantyltripeptidesRosana Ribić 1 , Lidija Habjanec 2 , Branka Vranešić 2 , Ruža Frkanec 2 ,and Srđanka Tomić-Pisarović 11 Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac102a, Zagreb, 10000, Croatia; 2 Institute of Immunology Inc., Rockefellerova 10,Zagreb, 10000, CroatiaIntroductionThe aim of this work was to compare the immunomodulating activity of adamantyltripeptidesD/L-(adamant-1-yl)Gly-L-Ala-D-isoGln (Ad 1 TP1 and Ad 1 TP2) and D/L-(adamant-2-yl)Gly-L-Ala-D-isoGln (Ad 2 TP1 and Ad 2 TP2) and their mannosyl derivatives.Structure-activity relationship was studied with respect to the absolute configuration ofmannose molecule, chiral spacer and adamantyltripeptides molecules. Adjuvant activitywas assessed for these novel compounds and compared to the previously known activity ofpeptidoglycan monomer (PGM, β-D-GlcNAc-(1→4)-D-MurNAc-L-Ala-D-isoGlnmesoDAP(εNH2 )-D-Ala-D-Ala) [1]. We have demonstrated in our previous investigationsthat the adamantyltripeptides (Ad 2 TP1 and Ad 2 TP2), structurally related to bacterialpeptidoglycans, have different biological activity, especially adjuvanticity [1,2].Results and DiscussionH OH OO HO HOOC H 3 O CHH3 O* HN **N *NOHHO R O CONH 2R = A d a m a n t - 1 - y l ; Adamant-2-ylFig. 1. Mannosyl derivatives of adamantyl-tripeptides;α-D-Man-(R/S)-OCH 2 CH(CH 3 )CO-D/L-(adamant-1-yl)Gly-L-Ala-D-isoGln and α-D-Man-(R/S)-OCH 2 CH(CH 3 )CO-D/L-(ada mant-2-yl)Gly-L-Ala-D-isoGln.anti-OVA IgG (AU/ml)3753503253002752502252001751501251007550250*0 1 2 3 4 5 6 7 8 9 10 11*anti-OVA IgG1 (AU/ml)800070006000500040003000200010000α-D-Mannose was coupled to D/L-(adamant-1-yl)Gly-L-Ala-D-isoGln (Ad 1 TP1 andAd 1 TP2) and D/L-(adamant-2-yl)Gly-L-Ala-D-isoGln (Ad 2 TP1 and Ad 2 TP2) via chirallinker (HOCH 2 CH(CH 3 )COOCH 3 , linker)(Figure 1) as previously described for PGM[3]. All tested compounds were characterizedby NMR and their purity was tested byHPLC. All examined compounds are watersoluble,non-toxic and non-pyrogenicsubstances. The adjuvant effect of prepareddiastereoisomers was tested on CBA micewith ovalbumin (OVA) as a model antigenand compared to the adjuvant effect of PGM*0 1 2 3 4 5 6 7 8 9 10 11*200* *anti-OVA IgG2a (AU/ml)17515012510075502500 1 2 3 4 5 6 7 8 9 10 11Fig. 2. The effect of examined compounds on the production of total anti-OVA IgG (a - left)and its subtypes IgG1 (b - middle) and IgG2a (c - right) after second booster. Experimentalgroups (X-axis) 1. OVA;2. OVA + PGM ; 3. OVA + Ad 1 TP1;4. OVA + α-D-Man-R-linker-Ad 1 TP1; 5. OVA + Ad 1 TP2; 6. OVA + α-D-Man-R-linker-Ad 1 TP2; 7. OVA + α-D- Man-Slinker-Ad1 TP2; 8. OVA + Ad 2 TP1; 9. OVA + Ad 2 TP2; 10. OVA + α-D-Man-R-linker-Ad 2 TP2; 11. OVA + α-D-Man-S-linker-Ad 2 TP2. • denotes group mean value, ο denotes eachserum separately. * p