Structure-Activity Relationship Studies of Retro-1 Analogues against Shiga Toxin

J Med Chem. 2020 Aug 13;63(15):8114-8133. doi: 10.1021/acs.jmedchem.0c00298. Epub 2020 Jul 27.

Abstract

High-throughput screening has shown that Retro-1 inhibits ricin and Shiga toxins by diminishing their intracellular trafficking via the retrograde route, from early endosomes to the Golgi apparatus. To improve the activity of Retro-1, a structure-activity relationship (SAR) study was undertaken and yielded an analogue with a roughly 70-fold better half-maximal effective concentration (EC50) against Shiga toxin cytotoxicity measured in a cell protein synthesis assay.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzodiazepinones / chemistry*
  • Benzodiazepinones / pharmacology*
  • Golgi Apparatus / drug effects
  • Golgi Apparatus / metabolism
  • HeLa Cells
  • Humans
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Shiga Toxins / antagonists & inhibitors*
  • Shiga Toxins / metabolism
  • Structure-Activity Relationship

Substances

  • 7-bromo-5-phenyl-4-propionyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one
  • Benzodiazepinones
  • Shiga Toxins