2. Academic Validation
  3. DABMA: A Derivative of ABMA with Improved Broad-Spectrum Inhibitory Activity of Toxins and Viruses

DABMA: A Derivative of ABMA with Improved Broad-Spectrum Inhibitory Activity of Toxins and Viruses

  • ACS Med Chem Lett. 2019 Jul 2;10(8):1140-1147. doi: 10.1021/acsmedchemlett.9b00155.
Yu Wu 1,  Valérie Pons 2,  Romain Noël 2,  Sabrina Kali 3,  Olena Shtanko 4,  Robert A Davey 5,  Michel R Popoff 6,  Noël Tordo 3,  Daniel Gillet 1,  Jean-Christophe Cintrat 2,  Julien Barbier 1
Affiliations

Affiliations

  • 1 Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette, France.
  • 2 Service de Chimie Bio-organique et de Marquage (SCBM), CEA, Université Paris-Saclay, LabEx LERMIT, 91191 Gif-sur-Yvette, France.
  • 3 Antiviral Strategies Unit, Virology Department, Institut Pasteur, 75015 Paris, France.
  • 4 Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, Texas 78227, United States.
  • 5 Department of Microbiology, NEIDL, Boston University, Boston, Massachusetts 02118, United States.
  • 6 Bactéries anaérobies et Toxines, Institut Pasteur, 75015 Paris, France.
PMID: 31413797 DOI: 10.1021/acsmedchemlett.9b00155
Abstract

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 Clostridium difficile toxin B (TcdB), Clostridium sordellii lethal toxin (TcsL), Pseudomonas 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.

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