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Research work on Myelin: In our studies, we demonstrated that linear peptide MBP 83-99(P1) [7], linear peptide MBP 87-99 (P2) [8], the mutated MBP 87-99 [A 91 , A 96 ] (P3) and itsrationally designed cyclic counterpart cyclo(87-99) MBP 87-99 [A 91 , A 96 ] (P4) [9] binds toHLA-DR4 which is consistent with our previous findings that cyclic peptides bind to HLA-DR4 and induces Th1 cytokines (IFN-γ, IL-2,). Furthermore, we demonstrated thatmannosylation with reduced mannan of linear peptides P1 and P2 diverts immuneresponses from Th1 to Th2 in SJL/J mice. This switch taken together with HLA bindingdata of mutated peptides P2, P3 render conjugated P4 as possible candidates for MStherapy. Wild type P2 and linear mutant P3 and P4 with substitution at positions 91,96critical for TCR contact were evaluated for their effects on the cytokine secretion by PBMCculture derived from 13 MS patients and their ability to induce Th1 / Th2 pathways. Inparticular, linear P1 in preliminary bioassays induced experimental allergic encephalomyelitis(EAE) while mutant linear P2 and cyclic P3 peptides suppressed disease. Previousstudies [8] in SJL/J mice have shown that conjugation of P1, P2, P3 to reduced mannandiverted immune responses to Th2 and generated antibodies which did not cross react withnative MBP protein. A recent successful clinical trial phase III, with linear sequence MBP82-98 (Dirucotide) [10] showed delay of disease progression in an HLA Class II on patientswith progressive multiple sclerosis. These results and ours overwhelmingly justify ourstudies with cyclic MBP analogues and may open the avenues for more effective, morestable therapeutics in treating disease.AcknowledgmentsWe thank ELDRUG S. A., Patras Science Park, Greece as well as VIANEX Pharmaceutical Companyfor financial support.References1. Carini, D.J., et al. J. Med. Chem. 34, 2525-2546 (1991).2. Matsoukas, J.M., et al. J. Med. Chem. 36, 904-911 (1993).3. Matsoukas, J.M., et al. Peptides 11, 367-374 (1990).4. Agelis, G., et al. J. Comput.-Aided Mol. Des. 24, 749-758 (2010).5. Agelis, G., et al. Amino Acids 2010 In press.6. Katsara, M., et al. Cur. Med. Chem. 13, 2221-2232 (2006).7. Matsoukas, J., et al. J. Med. Chem. 48, 1470-80, (2005).8. Katsara, M., et al. J. Med. Chem. 51, 3971-3978 (2008).9. Katsara, M., et al. J. Med. Chem. 52, 214-218 (2009).10. Krantz, M., et al. Eur. J. Neurol. 13, 887-95 (2006).245