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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010Dimerization of the Immunosuppressory DecapeptideUbiquitin FragmentMarzena Cydzik 1 , Monika Biernat 1 , Alicja Kluczyk 1 ,Piotr Stefanowicz 1 , Remigiusz Bąchor 1 , Michał Zimecki 2 ,and Zbigniew Szewczuk 11 Faculty of Chemistry, Wroclaw University, Wroclaw, 50-383, Poland; 2 Institute ofImmunology and Experimental Therapy, PAS, Wroclaw, 53-114, PolandIntroductionDimerization of the receptors is an essential step of various cellular signal transductionprocesses. Therefore, substances that are able to modulate the receptor dimerization maycontrol such a process and affect biological activities. Properly designed analogs of dimericligands were found to enhance interactions between two neighboring receptors with parallelor anti-parallel orientation [1,2].Ubiquitin is a highly conserved 76-amino acid polypeptide present in all eukaryoticcells. The polypeptide is involved in many key processes of cell biology. It has beenpostulated that ubiquitin originating cryptides could interfere in the ubiquitination process,affecting some ubiquitin activities [3]. Recently we found that ubiquitin fragments exhibitstrong immunosuppressive activity, comparable to that of cyclosporine A [4,5]. Ubiquitin isknown to exist in oligomeric form which can interact with various oligomeric receptors.However, the biological significance of some interactions of oligomeric ubiquitin stillremains unknown. It may be concluded that the dimeric analogs of ubiquitin fragments areable to interact with the dimeric receptors, which may cause modulation of interaction ofoligoubiquitin with the oligomeric receptors.Results and DiscussionWe designed and synthesized new dimeric analogs of the ubiquitin fragment, to probewhether the ubiquitin receptors may form oligomeric structures. Three dimerizationstrategies: N-terminus to N-terminus (compound 1), C-terminus to C-terminus (compound2) and head to tail (compounds 3 and 4) (Figure 1) were used to synthesize the dimericpeptides on solid support. We selected polyethylene glycol derivatives as cross-linkingreagents because of their flexibility, solubility and bioavailability. In the course of ourresearch, we developed a new and straightforward procedure for the direct dimerization ofthe C-terminal residues of peptide by their side-chains on solid support using apolyethylene glycol spacer.-Leu-Thr -Leu -Ser-Glu-Arg-Asp-Asp -Gly-Tyr-OHH-Leu-Thr -Leu -Ser-Glu-Arg-Asp-Asp -Gly-Lys56 Åhead to headtail to tail-Leu-Thr -Leu -SerH-Leu-Thr -Leu -Ser-Glu-Arg-Asp-Glu-Arg-Asp-Asp -Gly-Tyr-OH-Asp -Gly-Lyscompound 1 compound 256 ÅH-Leu-Thr -Leu -Ser-Glu-Arg-Asp-Asp -Gly-Tyrhead to tail28 Å / 56 Åcompound 3 / compound 4-Leu-Thr -Leu -Ser-Glu-Arg-Asp-Asp -Gly-Tyr-OHFig. 1. Three ways of dimerization of the immunosuppressive ubiquitin fragment.Calculated length of the PEG-linker is given.96