Tapeinou Anthi, Giannopoulou Efstathia, Simal Carmen, Hansen Bjarke E, Kalofonos Haralabos, Apostolopoulos Vasso, Vlamis-Gardikas Alexios, Tselios Theodore
Department of Chemistry, University of Patras, GR-26504, Rion, Greece.
Clinical Oncology Laboratory, University Hospital of Patras, Patras Medical School, GR-26504, Rion, Greece.
Eur J Med Chem. 2018 Jan 1;143:621-631. doi: 10.1016/j.ejmech.2017.11.063. Epub 2017 Nov 24.
Anthraquinone type compounds, especially di-substituted amino alkylamino anthraquinones have been widely studied as immunosuppressants. The anthraquinone ring is part of mitoxandrone that has been used for the treatment of multiple sclerosis (MS) and several types of tumors. A desired approach for the treatment of MS would be the immunosuppression and elimination of specific T cells that are responsible for the induction of the disease. Herein, the development of a peptide compound bearing an anthraquinone derivative with the potential to specifically destroy the encephalitogenic T cells responsible for the onset of MS is described. The compound consists of the myelin basic protein (MBP) 85-99 immunodominant epitope (MBP) coupled to an anthraquinone type molecule (AQ) via a disulfide (S-S) and 6 amino hexanoic acid (Ahx) residues (AQ-S-S-(Ahx)MBP). AQ-S-S-(Ahx)MBP could bind to HLA II DRB1*-1501 antigen with reasonable affinity (IC of 56 nM) The compound was localized to the nucleus of Jurkat cells (an immortalized line of human T lymphocytes) 10 min after its addition to the medium and resulted in lowered Bcl-2 levels (apoptosis). Entrance of the compound was abolished when cells were pre-treated with cisplatin, an inhibitor of thioredoxin reductase. Accordingly, levels of free thiols were elevated in the culture supernatants of Jurkat cells exposed to N-succinimidyl 3-(2-pyridyldithio) propionate coupled to (Ahx)MBP via a disulphide (SPDP-S-S-(Ahx)MBP) but returned to normal after exposure to cisplatin. These results raise the possibility of AQ-S-S-(Ahx)MBP being used as an eliminator of encephalitogenic T cells via implication of the thioredoxin system for the generation of the toxic, thiol-containing moiety (AQ-SH). Future experiments would ideally determine whether SPDP-S-S-(Ahx)MBP could incorporate into HLA II DRB1*-1501 tetramers and neutralize encephalitogenic T cell lines sensitized to MBP.
蒽醌类化合物，尤其是二取代氨基烷基氨基蒽醌，作为免疫抑制剂已被广泛研究。蒽醌环是米托蒽醌的一部分，米托蒽醌已被用于治疗多发性硬化症（MS）和几种类型的肿瘤。治疗MS的理想方法是免疫抑制并消除引发该疾病的特定T细胞。在此，描述了一种带有蒽醌衍生物的肽化合物的开发，该化合物具有特异性破坏引发MS的致脑炎性T细胞的潜力。该化合物由髓鞘碱性蛋白（MBP）85 - 99免疫显性表位（MBP）通过二硫键（S - S）与蒽醌类分子（AQ）以及6个氨基己酸（Ahx）残基偶联而成（AQ - S - S - (Ahx)MBP）。AQ - S - S - (Ahx)MBP能够以合理的亲和力（IC为56 nM）与HLA II DRB1* - 1501抗原结合。该化合物添加到培养基中10分钟后定位于Jurkat细胞（人T淋巴细胞的永生化细胞系）的细胞核中，并导致Bcl - 2水平降低（凋亡）。当用硫氧还蛋白还原酶抑制剂顺铂对细胞进行预处理时，该化合物的进入被阻断。因此，在暴露于通过二硫键与（Ahx）MBP偶联的N - 琥珀酰亚胺基3 - （2 - 吡啶基二硫代）丙酸酯（SPDP - S - S - (Ahx)MBP）的Jurkat细胞培养上清液中，游离巯基水平升高，但在暴露于顺铂后恢复正常。这些结果增加了AQ - S - S - (Ahx)MBP通过硫氧还蛋白系统生成有毒的含巯基部分（AQ - SH）而被用作致脑炎性T细胞消除剂的可能性。未来的实验理想情况下将确定SPDP - S - S - (Ahx)MBP是否能够掺入HLA II DRB1* - 1501四聚体中并中和对MBP敏感的致脑炎性T细胞系。
