Tagliavini F, Forloni G, Colombo L, Rossi G, Girola L, Canciani B, Angeretti N, Giampaolo L, Peressini E, Awan T, De Gioia L, Ragg E, Bugiani O, Salmona M
Istituto Nazionale Neurologico Carlo Besta, Via Celoria 11, Milano, 20133, Italy.
J Mol Biol. 2000 Jul 28;300(5):1309-22. doi: 10.1006/jmbi.2000.3840.
Prion diseases are characterized by the accumulation of altered forms of the prion protein (termed PrP(Sc)) in the brain. Unlike the normal protein, PrP(Sc) isoforms have a high content of beta-sheet secondary structure, are protease-resistant, and form insoluble aggregates and amyloid fibrils. Evidence indicates that they are responsible for neuropathological changes (i.e. nerve cell degeneration and glial cell activation) and transmissibility of the disease process. Here, we show that the antibiotic tetracycline: (i) binds to amyloid fibrils generated by synthetic peptides corresponding to residues 106-126 and 82-146 of human PrP; (ii) hinders assembly of these peptides into amyloid fibrils; (iii) reverts the protease resistance of PrP peptide aggregates and PrP(Sc) extracted from brain tissue of patients with Creutzfeldt-Jakob disease; (iv) prevents neuronal death and astrocyte proliferation induced by PrP peptides in vitro. NMR spectroscopy revealed several through-space interactions between aromatic protons of tetracycline and side-chain protons of Ala(117-119), Val(121-122) and Leu(125) of PrP 106-126. These properties make tetracycline a prototype of compounds with the potential of inactivating the pathogenic forms of PrP.
朊病毒疾病的特征是大脑中异常形式的朊病毒蛋白（称为PrP(Sc)）的积累。与正常蛋白质不同，PrP(Sc)异构体具有高含量的β-折叠二级结构，具有蛋白酶抗性，并形成不溶性聚集体和淀粉样纤维。有证据表明，它们是神经病理变化（即神经细胞变性和胶质细胞活化）以及疾病过程传播性的原因。在此，我们表明抗生素四环素：(i) 与对应于人类PrP 106-126和82-146残基的合成肽产生的淀粉样纤维结合；(ii) 阻碍这些肽组装成淀粉样纤维；(iii) 恢复从克雅氏病患者脑组织中提取的PrP肽聚集体和PrP(Sc)的蛋白酶抗性；(iv) 在体外防止PrP肽诱导的神经元死亡和星形胶质细胞增殖。核磁共振光谱揭示了四环素的芳香族质子与PrP 106-126的Ala(117-119)、Val(121-122)和Leu(125)侧链质子之间的几种空间相互作用。这些特性使四环素成为具有使PrP致病形式失活潜力的化合物的原型。
