Wu Yu, Pons Valérie, Noël Romain, Kali Sabrina, Shtanko Olena, Davey Robert A, Popoff Michel R, Tordo Noël, Gillet Daniel, Cintrat Jean-Christophe, Barbier Julien
Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette, France.
Service de Chimie Bio-organique et de Marquage (SCBM), CEA, Université Paris-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette, France.
ACS Med Chem Lett. 2019 Jul 2;10(8):1140-1147. doi: 10.1021/acsmedchemlett.9b00155. eCollection 2019 Aug 8.
The small molecule ABMA has been previously shown to protect cells against multiple toxins and pathogens including virus, intracellular bacteria, and parasite. Its mechanism of action is directly associated with host endolysosomal pathway rather than targeting toxin or pathogen itself. However, the relationship of its broad-spectrum anti-infection activity and chemical structure is not yet resolved. Here, we synthesized a series of derivatives and compared their activities against diphtheria toxin (DT). Dimethyl-ABMA (DABMA), one of the most potent analogs with about 20-fold improvement in protection efficacy against DT, was identified with a similar mechanism of action to ABMA. Moreover, DABMA exhibited enhanced efficacy against toxin B (TcdB), lethal toxin (TcsL), Exotoxin A (PE) as well as Rabies and Ebola viruses. The results revealed a structure-activity relationship of ABMA, which is a starting point for its clinical development as broad-spectrum drug against existing and emerging infectious diseases.
小分子ABMA先前已被证明可保护细胞免受多种毒素和病原体的侵害，包括病毒、细胞内细菌和寄生虫。其作用机制与宿主内溶酶体途径直接相关，而非靶向毒素或病原体本身。然而，其广谱抗感染活性与化学结构之间的关系尚未明确。在此，我们合成了一系列衍生物，并比较了它们对白喉毒素（DT）的活性。二甲基-ABMA（DABMA）是最有效的类似物之一，对DT的保护效果提高了约20倍，其作用机制与ABMA相似。此外，DABMA对毒素B（TcdB）、致死毒素（TcsL）、外毒素A（PE）以及狂犬病病毒和埃博拉病毒均表现出增强的疗效。这些结果揭示了ABMA的构效关系，这是其作为针对现有和新出现传染病的广谱药物进行临床开发的起点。
