Treatment of experimental allergic encephalomyelitis (EAE) by a rationally designed cyclic analogue of myelin basic protein (MBP) epitope 72–85

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

“…Related work in our laboratory has led to the design and synthesis of cyclic analogues for guinea pig MBP 72-85 , Thrombin receptor motif SFLLR, Angiotensins II and III, and GnRH (unpublished) which were able to maintain or suppress the biological function of the original peptide. 15,20,[23][24][25][26][27][28] We had previously demonstrated that injection of Lewis rats with linear or cyclic guinea pig MBP 72-85 peptides induced EAE. 19 15 In our in vivo rat studies, EAE was induced by the agonist guinea pig epitope MBP [72][73][74][75][76][77][78][79][80][81][82][83][84][85] and not by the human MBP 83-99 agonist peptide.…”

Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

“…Effort must be made to understand: (a) the forces that determine the folding of the epitope; (b) the conservation of the linearity and extended structure of the altered epitope; (c) the molecular features of the altered epitope that maximize the productive interactions with HLA-DR2 and minimize the contacts with TCR. The linear peptides were prepared on 2-chlorotrityl chloride resin (CLTR-Cl) using the Fmoc/tBu solid-phase methodology [28][29][30][31]. The first N a Fmoc (9-fluorenylmethyloxycarboxyl)-protected amino acid (Fmoc-Pro-OH) was esterified to the resin in the presence of diisopropylethylamine (DIPEA) in dichloromethane (DCM) in 1 h at RT [28][29][30][31].…”

“…The linear peptides were prepared on 2-chlorotrityl chloride resin (CLTR-Cl) using the Fmoc/tBu solid-phase methodology [28][29][30][31]. The first N a Fmoc (9-fluorenylmethyloxycarboxyl)-protected amino acid (Fmoc-Pro-OH) was esterified to the resin in the presence of diisopropylethylamine (DIPEA) in dichloromethane (DCM) in 1 h at RT [28][29][30][31]. DCM/MeOH/DIPEA (85:10:5) was then added and the resulting mixture was stirred for another 10 min at RT.…”

“…DCM/MeOH/DIPEA (85:10:5) was then added and the resulting mixture was stirred for another 10 min at RT. The remaining protected peptide chains were assembled by sequential couplings of the appropriate Fmoc protected amino acids (2.5 equiv), in the presence of N,N'-diisopropylcarbodiimide (DIC) (2.75 equiv) and 1-hydroxybenzotriazole (HOBt) (3.75 equiv) in N,N-dimethylformamide (DMF) [28][29][30][31]. The completeness of each coupling was verified by the Kaiser test and TLC using a BAW, 4:1:1 (v/v/v) eluent system and the Fmoc protecting group was removed by treatment with piperidine solution (20% in DMF).…”

“…NMR spectroscopy is coupled with MD simulations to study the binding motif of the altered peptide epitopes of MBP 83-99 with HLA-DR2 [19][20][21][22][23][24][25][26][27][28][29][30][31].…”