Role of myelin basic protein epitope MBP74‐85 in experimental autoimmune encephalomyelitis: Elaboration of agonist and antagonist motifs

Conformational properties of the myelin basic protein epitope QKSQRSQDENPV (MBP_74‐85) which can initiate experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis, were investigated by semiempirical methods. Energy calculations were carried out on the full MBP_74‐85 autoantigen and the antagonist analog [Ala⁸¹]MBP_74‐85. These studies have revealed a low energy cyclic conformation for MBP_74‐85 which is characterized by an agonist motif comprising an interaction of the sidechains of Arg⁷⁸ and Asp⁸¹ of MBP_74‐85. Disruption of this agonist motif by removal of the residue 81 carboxylate, as in the antagonist [Ala⁸¹]MBP_74‐85, invokes a compensatory rearrangement of the molecule resulting in interaction of the Arg⁷⁸ sidechain with the sidechain of Glu⁸² together with Lys⁷⁵. This antagonist motif, comprising guanidino, amino, and carboxylate groups, has been reproduced previously in semimimetic peptides having the general structure Ser‐Arg‐LINKER‐Glu‐NH₂ (where LINKER = one or more residues of aminocaproic acid or isonipecotic acid), which have preferred conformations characterized by interaction of the carboxylate with both the guanidino and amino groups in a similar manner to the antagonist motif in [Ala⁸¹]MBP_74‐85. However, in EAE assays these small semimimetics turned out to be partial agonists, i.e., molecules with structures between agonists and antagonists. These findings provide insight into the design of small molecule (orally active) autoantigen antagonists for the treatment of autoimmune diseases such as MS. Drug Dev. Res. 48:1–5, 1999. © 1999 Wiley‐Liss, Inc.