Aza-Altered Peptides for the Treatment of Multiple Sclerosis

Myelin basic protein (MBP) is a major target of Tcells in lesions of multiple sclerosis (MS) patients and the closely related animal model, experimental autoimmune encephalomyelitis (EAE).   Interactions between the major histocombatability complex II containing antigenic peptides and the Tcell receptor activate CD4+ Tcells that perpetuate EAE and MS.  It has been previously shown treating with an altered peptide ligand (APL) in which the normal antigenic sequence has been slightly changed at Tcell contact positions is helpful in reducing disease in both rodents and humans.  The use of natural peptides, which are susceptible to protease degradation, requires high concentrations that can create hypersensitivity reactions.  Hypothesis: APL containing aza substitutions, CH(R)-N -> N(R)N, could lead to better protease resistance, reduced clinical disease scores and a shift in Tcell pro file. The aza-APL and other controls were synthesized using solid-phase synthesis and tested for binding kinetics and serum degradation.  The best aza-APL candidate was given as a treatment in B10.PL mice treated with MBP to induce EAE. Clinical scores and evaluation of spinal cords and Tcells were used to determine disease reduction.  Results: Aza-APLs show increase in binding kinetics as compared to the native MBP peptide and an increased protease resistance as compared to previous APLs.  In the EAE mice, aza-APL treatment shows a decrease of clinical disease scores, decreased signs of demyelination and an anti-inflammatory change in the Tcell profile.  Conclusion:  Aza-APLs have increased protease resistance and are effective in reducing clinical and internal signs of disease in EAE animals.