Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 127 Vasilissis Sophias Ave., 11521 Athens, Greece.
Department of Chemistry, University of Patras, 26504 Patras, Greece.
Molecules. 2018 Jan 31;23(2):304. doi: 10.3390/molecules23020304.
In this report, amide-linked cyclic peptide analogues of the 87-99 myelin basic protein (MBP) epitope, a candidate autoantigen in multiple sclerosis (MS), are tested for therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). Cyclic altered peptide analogues of MBP with substitutions at positions 91 and/or 96 were tested for protective effects when administered using prophylactic or early therapeutic protocols in MBP-induced EAE in Lewis rats. The Lys and Pro of MBP are crucial T-cell receptor (TCR) anchors and participate in the formation of trimolecular complex between the TCR-antigen (peptide)-MHC (major histocompability complex) for the stimulation of encephalitogenic T cells that are necessary for EAE induction and are implicated in MS. The cyclic peptides were synthesized using Solid Phase Peptide Synthesis (SPPS) applied on the 9-fluorenylmethyloxycarboxyl/tert-butyl Fmoc/tBu methodology and combined with the 2-chlorotrityl chloride resin (CLTR-Cl). Cyclo(91-99)[Ala]MBP, cyclo(87-99)[Ala]MBP and cyclo(87-99)[Arg, Ala]MBP, but not wild-type linear MBP, strongly inhibited MBP-induced EAE in Lewis rats when administered using prophylactic and early therapeutic vaccination protocols. In particular, cyclo(87-99)[Arg, Ala]MBP was highly effective in preventing the onset and development of clinical symptoms and spinal cord pathology and providing lasting protection against EAE induction.
在本报告中，对髓鞘碱性蛋白（MBP）表位的酰胺连接环肽类似物进行了测试，该表位是多发性硬化症（MS）中的候选自身抗原，以评估其在实验性自身免疫性脑脊髓炎（EAE）中的治疗效果。在 Lewis 大鼠的 MBP 诱导的 EAE 中，使用预防性或早期治疗方案，对位置 91 和/或 96 发生取代的 MBP 环改变肽类似物进行了保护性作用测试。MBP 的 Lys 和 Pro 是关键的 T 细胞受体（TCR）锚点，并参与 TCR-抗原（肽）-MHC（主要组织相容性复合体）的三聚体复合物形成，以刺激引发 EAE 诱导的致脑炎 T 细胞，这些细胞与 MS 有关。使用固相肽合成（SPPS），并结合 2-氯三苯甲基氯树脂（CLTR-Cl），按照 9-芴甲氧羰基/叔丁基 Fmoc/tBu 方法，合成了环肽。当使用预防性和早期治疗性疫苗接种方案时，环（91-99）[Ala]MBP、环（87-99）[Ala]MBP 和环（87-99）[Arg，Ala]MBP 但不是野生型线性 MBP，强烈抑制了 Lewis 大鼠的 MBP 诱导的 EAE。特别是，环（87-99）[Arg，Ala]MBP 在预防临床症状和脊髓病理学的发生和发展以及提供对 EAE 诱导的持久保护方面非常有效。
Zotero 插件