Homo-β-amino acid containing MBP(85-99) analogs alleviate experimental autoimmune encephalomyelitis.

Ravi Kant,Shweta Pasi,Avadhesha Surolia

doi:10.1038/srep08205

Abstract

MBP(85–99), an immuno-dominant epitope of myelin basic protein which binds to the major histocompatibility complex haplotype HLA-DR2 is widely implicated in the pathogenesis of multiple sclerosis. J5, an antagonist of MBP(85–99), that blocks the binding of MBP(85–99) to soluble HLA-DR2b much more efficiently than glatiramer acetate (a random copolymer comprising major MHC and T-cell receptor contact residues), was transformed into analogs with superior biological half-lives and antagonistic-activities by substitution of some of its residues with homo-β-amino acids. S18, the best analog obtained ameliorated symptoms of experimental autoimmune encephalomyelitis at least twice more effectively than glatiramer acetate or J5. S18 displayed marked resistance to proteolysis in-vitro; biological impact of which was evident in the form of delayed clinical onset of disease and prolonged therapeutic-benefits. Besides active suppression of MBP(85–99)-reactive CD4+ T-cells in-vitro and in-vivo S18 treatment also generated IL-4 producing CD4+ T-cell clones, through which protective effect could be transferred passively.

Highlights

MBP(85–99), an immuno-dominant epitope of myelin basic protein which binds to the major histocompatibility complex haplotype HLA-DR2 is widely implicated in the pathogenesis of multiple sclerosis
Homo-b-amino acid substituted analogs of MBP(85–99): Design, synthesis and inhibition analysis. We initiated these studies with J5, one of the best known antagonist of MBP(85–99)
Amino acid residues at penultimate positions i.e. P10 and P-2 have been exchanged with prolines (Ps), since they are known for their ability to resist degradation by exo-peptidases (Supplementary Fig. S1)

Summary

Correspondence and requests for materials should be addressed to

J5, an antagonist of MBP(85–99), that blocks the binding of MBP(85–99) to soluble HLA-DR2b much more efficiently than glatiramer acetate (a random copolymer comprising major MHC and T-cell receptor contact residues), was transformed into analogs with superior biological half-lives and antagonistic-activities by substitution of some of its residues with homo-b-amino acids. Various components of pathogenic process have been targeted for designing therapeutic strategies such as: presentation of myelin antigens to auto-reactive T-cells, their activation, egress from lymph nodes, migration across vasculature and blood brain barrier[16,17]. Certain residues in J5, the best known MBP(85–99) antagonist, were replaced with their homo-b-counterparts to obtain antagonists with far superior stability and antagonistic activities, features that eventually translated into 1.5 to 2 fold enhancement of therapeutic efficacy in experimental models of MS

Results

Discussion

Methods

Additional information