Institute for Novel and Emerging Infectious Diseases at the Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health Südufer 10, 17493 Greifswald-Insel Riems, Germany.
Antimicrob Agents Chemother. 2011 Oct;55(10):4774-81. doi: 10.1128/AAC.00151-11. Epub 2011 Jul 11.
Transmissible spongiform encephalopathies (TSEs) represent a group of fatal neurodegenerative disorders that can be transmitted by natural infection or inoculation. TSEs include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. The emergence of a variant form of CJD (vCJD), which has been associated with BSE, produced strong pressure to search for effective treatments with new drugs. Up to now, however, TSEs have proved incurable, although many efforts have been made both in vitro and in vivo to search for potent therapeutic and prophylactic compounds. For this purpose, we analyzed a compound library consisting of 10,000 compounds with a cell-based high-throughput screening assay dealing with scrapie-infected scrapie mouse brain and ScN(2)A cells and identified a new class of inhibitors consisting of 3,5-diphenylpyrazole (DPP) derivatives. The most effective DPP derivative showed half-maximal inhibition of PrP(Sc) formation at concentrations (IC(50)) of 0.6 and 1.2 μM, respectively. This compound was subsequently subjected to a number of animal experiments using scrapie-infected wild-type C57BL/6 and transgenic Tga20 mice. The DPP derivative induced a significant increase of incubation time both in therapeutic and prophylactic experiments. The onset of the prion disease was delayed by 37 days after intraperitoneal and 42 days after oral application, respectively. In summary, we demonstrate a high in vitro efficiency of DPP derivatives against prion infections that was substantiated in vivo for one of these compounds. These results indicate that the novel class of DPP compounds should comprise excellent candidates for future therapeutic studies.
传染性海绵状脑病（TSE）代表了一组致命的神经退行性疾病，可通过自然感染或接种传播。TSE 包括绵羊的瘙痒病、牛的海绵状脑病（BSE）和人类的克雅氏病（CJD）。一种变异型 CJD（vCJD）的出现与 BSE 有关，这给寻找有效的新型药物治疗带来了巨大压力。然而，迄今为止，TSE 已被证明是无法治愈的，尽管在体外和体内都进行了许多努力来寻找有效的治疗和预防化合物。为此，我们分析了一个由 10000 种化合物组成的化合物库，该库通过一种基于细胞的高通量筛选测定法来处理感染瘙痒病的瘙痒病鼠脑和 ScN(2)A 细胞，并鉴定出一类新的抑制剂，由 3,5-二苯基吡唑（DPP）衍生物组成。最有效的 DPP 衍生物在浓度（IC50）分别为 0.6 和 1.2 μM 时对 PrP(Sc)形成的半最大抑制作用。随后，该化合物在感染瘙痒病的野生型 C57BL/6 和转基因 Tga20 小鼠中进行了一系列动物实验。在治疗和预防实验中，DPP 衍生物均能显著延长潜伏期。经腹腔内和口服给药后，PrP 病的发病分别延迟了 37 天和 42 天。总之，我们证明了 DPP 衍生物在体外对朊病毒感染的高效性，其中一种化合物在体内得到了证实。这些结果表明，新型 DPP 化合物应成为未来治疗研究的优秀候选物。
