Putative Bioactive Conformations of Amide Linked Cyclic Myelin Basic Protein Peptide Analogues Associated with Experimental Autoimmune Encephalomyelitis

• Published in: Journal of medicinal chemistry Vol. 50; no. 24; pp. 6039 - 6047
• Main Authors: Spyranti, Zinovia, Dalkas, Georgios A, Spyroulias, Georgios A, Mantzourani, Efthimia D, Mavromoustakos, Thomas, Friligou, Irene, Matsoukas, John M, Tselios, Theodore V
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 29.11.2007
• Subjects: Biological and medical sciences; Cyclization; Deuterium; Dimethyl Sulfoxide; Encephalomyelitis, Autoimmune, Experimental - metabolism; Magnetic Resonance Spectroscopy; Medical sciences; Models, Molecular; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Myelin Basic Protein - chemistry; Neurology; Peptides, Cyclic - chemistry; Protein Conformation; Solutions; Multiple sclerosis; Antigenic determinant; Encephalomyelitis; Oligopeptides; Peptides; Ligand; Cyclic peptides; Major histocompatibility system; Conformational analysis; Autoimmune disease; NMR spectrometry; Modeling; Inflammatory disease; Hydrogen 1; Structure activity relation; Molecular model; Pulse sequence; Immunopathology; Nervous system diseases; T cell receptor; Cerebral disorder; Two dimension spectrometry; Biological fixation; Central nervous system disease; Spinal cord disease
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070770m

The solution models of cyclo(87−99) MBP87 - 99, cyclo(87−99) [Ala91,96] MBP87 - 99, and cyclo(87−99) [Arg91, Ala96] MBP87 - 99 have been determined through 2D NMR spectroscopy in DMSO-d 6. Chemical shift analysis has been performed in an attempt to elucidate structural changes occurring upon substitution of native residues. NMR-derived geometrical constraints have been used in order to calculate high-resolution conformers of the above peptides. Conformational analysis of the three synthetic analogues show that the bioactivity, or the lack of it, may possibly be due to the distinct local structure observed and the subsequent differences in the overall topology and exposed area after binding with Major Histocompatibility Complex II (MHC II). It is believed that an overall larger solvent accessible area blocks the approach and binding of the T-cell receptor (TCR) on the altered peptide ligand (APL)−MHC complex, whereas more compact structures do not occlude weak interactions with an approaching TCR and can cause Experimental Autoimmune Encephalomyelitis (EAE) antagonism. A pharmacophore model based on the structural data has been generated.