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 (MBP74-85) which can initiate experimental autoimmune encephalitis (EAE), a n animal model of multiple sclerosis, were investigated by semiempirical me thods. Energy calculations were carried out on the full MBP74-85 autoantige n and the antagonist analog [Ala(81)]MBP74-85. These studies have revealed a low energy cyclic conformation for MBP74-85 which is characterized by an agonist motif comprising an interaction of the sidechains of Arg(78) and As p(81) of MBP74-85. Disruption of this agonist motif by removal of the resid ue 81 carboxylate, as in the antagonist [Ala(81)]MBP74-85, invokes a compen satory rearrangement of the molecule resulting in interaction of the Arg(78 ) sidechain with the sidechain of Glu together with Lys(75). This antagonis t motif, comprising guanidino, amino, and carboxylate groups, has been repr oduced previously in semimimetic peptides having the general structure Ser- Arg-LINKER-Glu-NH2 (where LINKER = one or more residues of aminocaproic aci d or isonipecotic acid), which have preferred conformations characterized b y interaction of the carboxy[ate with both the guanidino and amino groups i n a similar manner to the antagonist motif in [Ala(81)]MBP74-85. However, i n EAE assays these small semimimetics turned out to be partial agonists, i. e., molecules with structures between agonists and antagonists. These findi ngs provide insight into the design of small molecule (orally active) autoa ntigen antagonists for the treatment of autoimmune diseases such as MS. Dru g Dev. Res. 48:1-5, 1999. (C) 1999 Wiley-Liss, Inc.