Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, LabEx LERMIT, 91191, Gif-sur-Yvette, France.
Service de Chimie Bio-organique et Marquage (SCBM), CEA, Université Paris-Saclay, LabEx LERMIT, 91191, Gif-sur-Yvette, France.
Sci Rep. 2017 Nov 14;7(1):15567. doi: 10.1038/s41598-017-15466-7.
Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identified the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efficiently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad-spectrum compounds with therapeutic potential against diverse severe infectious diseases.
细胞内病原体和毒素利用宿主细胞机制进入细胞，发挥其有害作用，并劫持宿主营养物质来进行自身发展。一种潜在的治疗多种病原体感染的方法是使用靶向宿主成分的小分子药物。我们从基于细胞的高通量筛选中鉴定出化合物 1-金刚烷基（5-溴-2-甲氧基苄基）胺（ABMA），因为它能够保护人类细胞和小鼠免受蓖麻毒素的毒性侵害。该化合物能够有效保护细胞免受各种毒素和病原体的侵害，包括病毒、细胞内细菌和寄生虫。ABMA 在不影响其他细胞器（早期内体、溶酶体、高尔基体、内质网或细胞核）的情况下，引发哺乳动物细胞中 Rab7 阳性晚期内体隔室的积累。由于 ABMA 的作用机制仅限于宿主内体隔室，因此它可以减少依赖该途径入侵细胞的病原体对细胞的感染。ABMA 可能代表一类新型的广谱化合物，具有治疗多种严重传染病的潜力。
