Webb Sarah, Lekishvili Tamuna, Loeschner Corinna, Sellarajah Shane, Prelli Frances, Wisniewski Thomas, Gilbert Ian H, Brown David R
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
J Virol. 2007 Oct;81(19):10729-41. doi: 10.1128/JVI.01075-07. Epub 2007 Jul 25.
Prion diseases are fatal neurodegenerative disorders. Identification of possible therapeutic tools is important in the search for a potential treatment for these diseases. Congo red is an azo dye that has been used for many years to detect abnormal prion protein in the brains of diseased patients or animals. Congo red has little therapeutic potential for the treatment of these diseases due to toxicity and poor permeation of the blood-brain barrier. We have prepared two Congo red derivatives, designed without these liabilities, with potent activity in cellular models of prion disease. One of these compounds cured cells of the transmissible agent. The mechanism of action of these compounds is possibly multifactorial. The high affinity of Congo red derivatives, including compounds that are ineffective and are effective at the cure of prion disease, for abnormally folded prion protein suggests that the amyloidophylic property of these derivatives is not as critical to the mechanism of action as other effects. Congo red derivatives that are effective at the cure of prion disease increased the degradation of abnormal PrP by the proteasome. Therefore, the principal mechanism of action of the Congo red analogues was to prevent inhibition of proteasomal activity by PrPSc.
朊病毒疾病是致命的神经退行性疾病。在寻找这些疾病的潜在治疗方法时，确定可能的治疗工具很重要。刚果红是一种偶氮染料，多年来一直用于检测患病患者或动物大脑中的异常朊病毒蛋白。由于毒性和血脑屏障的低渗透性，刚果红对这些疾病的治疗几乎没有治疗潜力。我们制备了两种刚果红衍生物，设计时避免了这些缺点，在朊病毒疾病的细胞模型中具有强大的活性。其中一种化合物治愈了细胞中的传染性病原体。这些化合物的作用机制可能是多因素的。刚果红衍生物，包括对治疗朊病毒疾病无效和有效的化合物，对异常折叠的朊病毒蛋白具有高亲和力，这表明这些衍生物的嗜淀粉样特性对作用机制的重要性不如其他效应。能有效治疗朊病毒疾病的刚果红衍生物增加了蛋白酶体对异常PrP的降解。因此，刚果红类似物的主要作用机制是防止PrPSc对蛋白酶体活性的抑制。
