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

Abstract

Conformational properties of the myelin basic protein epitope QKSQRSQDENPV (MBP74‐85) 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 MBP74‐85 autoantigen and the antagonist analog [Ala81]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 Arg78 and Asp81 of MBP74‐85. Disruption of this agonist motif by removal of the residue 81 carboxylate, as in the antagonist [Ala81]MBP74‐85, 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]MBP74‐85. 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.

Design And Synthesis of a Novel Potent Myelin Basic Protein Epitope 87−99 Cyclic Analogue: Enhanced Stability and Biological Properties of Mimics Render Them a Potentially New Class of Immunomodulators

“…While mimetic strategy is a challenging perspective, it is worth pursuing in particular for MBP epitope-based MS therapy, as it is still in its infancy. Efforts to design semimimetics of MBP 72 - 85 epitope (the guinea pig epitope) by combining nonnatural amino acids (iNip, Acp) as spacers and MBP epitope immunophores (Ser, Arg, Glu, Ala, Gln) led to substances which were effective to some extent in inducing the onset of EAE. − Presently, our studies focus mainly on the design, synthesis, and evaluation of cyclic mimics not only as a step toward nonpeptide mimetics but also as putative therapeutics in MS. The advantages of using cyclic analogues compared to linear peptides include the following: (i) cyclic analogues are more stable and more resistant to enzymatic degradation; (ii) cyclization of amino acid sequences results in increased receptor selectivity, consequently resulting in an improved pharmacological profile; (iii) the conformation of cyclic analogues is locked compared to the conformational flexibility characterizing the linear counterpart, allowing identification of active sites; (iv) cyclic analogues are an important intermediate step and a useful template toward the rational design and development of a nonpeptide (mimetic) drug for oral administration; and (v) it is feasible that a cyclic peptide could be orally active if appropriately constrained.…”

Antagonistic Effects of Human Cyclic MBP87-99Altered Peptide Ligands in Experimental Allergic Encephalomyelitis and Human T-Cell Proliferation

“…In particular, cyclic peptides have been used in several cases as potent inhibitors of transcriptional activation by Tat protein in human cells, synthetic immunogens, antigens for herpes simplex virus, inhibitors against α-amylase, and protein stabilizers . For diabetes, a cyclic peptide protected mice from disease while the linear counterpart did not. , Even in its infancy, mimetic strategy is a challenging perspective for medicinal chemists and worth pursuing particularly for MBP epitope-based MS treatment. − …”

“…17,18 Even in its infancy, mimetic strategy is a challenging perspective for medicinal chemists and worth pursuing particularly for MBP epitope-based MS treatment. [19][20][21] In this study we developed antagonist cyclic analogues based on the immunodominant human MBP epitope 87-99 (MBP 87-99 ). In particular, two cyclic analogues, cyclo(91-99)[Ala 96 ]MBP 87-99 (P3) and cyclo-(87-99)[Arg 91 , Ala 96 ]MBP 87-99 (P4), have been designed on the basis of conformational studies carried out on MBP epitope 87-99 (P1) and its linear antagonist [Arg 91 , Ala 96 ]MBP 87-99 (P2), which has been recently shown to inhibit EAE induced in Lewis rats by the MBP 72-85 epitope.…”

Design, Synthesis, and Molecular Modeling of a Novel Amide-Linked Cyclic GnRH Analogue Cyclo(4−9)[Lys4,d-Trp6,Glu9]GnRH: Stimulation of Gonadotropin Gene Expression

“…Several linear analogues, triptorelin, leuprolide, buserelin, goserelin, nafarelin, histrelin, are known in clinical use for cancer treatment and reproductive disorders. The number of reported synthetic cyclic GnRH analogues is however limited. − Our experience in cyclization procedures has previously been applied to developing novel analogues of angiotensin, − myelin basic protein, − and thrombin receptor peptides (TRAPS), − which led us to pursue the synthesis of a rationally designed cyclic GnRH analogue. In this study we used linear salmon and chicken GnRH as control to test the activity of the synthesized GnRH analogue in goldfish in terms of gonadotropin subunit gene expression.…”