In:
Disease Models & Mechanisms, The Company of Biologists
Abstract:
Clostridium perfringens Epsilon toxin is categorized as third most lethal bioterrorism agent by CDC, with no therapeutic counter measures available for humans. Here we have developed a high affinity inhibitory compound by synthesizing and evaluating the structure activity relationship (SAR) of a library of diverse Glycosides 1-12. SAR of glycosides-Etx heptamer revealed exceptionally strong H-bond interactions of Glycoside-4 with a druggable pocket in the oligomerization and β-hairpin region of Etx. Analysis of its structure suggested that Glycoside-4 might self-aggregate to form a robust micelle like supra-molecular complex due to its linear side chain architecture, which was authenticated by fluorescence spectroscopy. Further, this micelle hinders the Etx monomer-monomer interaction required for oligomerization, validated by both surface plasmon resonance (SPR) and immunoblotting. This phenomenon in-turn leads to blockage of pore formation. Downstream evaluation revealed that Glycoside-4 effectively blocked cell death of Etx treated cultured primary cells and maintained cellular homeostasis; via disrupting oligomerization, blocking pore formation, restoring calcium homeostasis, stabilizing mitochondrial membrane and impairing HMGB1 translocation from nucleus–to-cytoplasm. Furthermore, a single dosage of Glycoside-4 protected the Etx-challenged mice and restored normal function to multiple organs. This work for the first-time reports a potent, nontoxic glycoside with strong ability to occlude toxin lethality representing it as bio-arm therapeutics against Etx-based biological threat.
Type of Medium:
Online Resource
ISSN:
1754-8411
,
1754-8403
Language:
English
Publisher:
The Company of Biologists
Publication Date:
2019
detail.hit.zdb_id:
2451104-3
