Hrabinova Martina, Pejchal Jaroslav, Kucera Tomas, Jun Daniel, Schmidt Monika, Soukup Ondrej
Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence in Brno, Hradec Kralove, Czech Republic.
Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.
Curr Neuropharmacol. 2021;19(1):61-77. doi: 10.2174/1570159X18666200503023323.
β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.
β-分泌酶（BACE1）被视为开发用于治疗阿尔茨海默病（AD）的降低β淀粉样蛋白（Aβ）药物的主要靶点。尽管该酶于1991年被发现，并有助于将Aβ假说作为AD发病机制的非常重要的特征之一，但利用BACE1抑制剂进行AD治疗的进展仍然有限。此外，在过去几年中，各大制药公司已停止了五种曾被强烈视为有前景的BACE1抑制剂的临床试验。在我们的综述中，描述了Aβ假说、该酶、其功能以及选定的底物。BACE1抑制剂分为四代。那些进行过临床试验的抑制剂显示出不良反应，包括体重减轻、皮疹、神经精神症状恶化等。一些抑制剂未能建立具有统计学意义的风险效益比，甚至比安慰剂的效果更差。我们仍然认为，靶向BACE1的药物可能仍有一些潜力，但现在应该采用不同的方法来抑制BACE1，或者将重点转移到调节其运输和/或翻译后修饰上。
