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Updated: Jul 2, 2026

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Published on: August 5, 2022

Isofagomine Derivatives as TcdB Glucosyltransferase Inhibitors.

Karl J Shaffer1, Nord Gilaj2, Andrew G Wagner2

  • 1Ferrier Research Institute, Victoria University of Wellington, Lower Hutt 5010, New Zealand.

Journal of Medicinal Chemistry
|July 1, 2026
PubMed
Summary
This summary is machine-generated.

New compounds were developed to inhibit Clostridioides difficile toxin B (TcdB), a key factor in severe diarrhea. Researchers explored modifications to isofagomine, aiming to enhance TcdB inhibition by targeting its catalytic site.

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Last Updated: Jul 2, 2026

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Published on: July 26, 2018

Area of Science:

  • Biochemistry
  • Microbiology
  • Drug Discovery

Background:

  • Clostridioides difficile (C. difficile) causes hospital-acquired diarrhea, with toxins TcdA and TcdB being major virulence factors.
  • Toxin B (TcdB) inactivates host GTPases via its glucosyltransferase domain (GTD), disrupting cellular integrity and driving disease.
  • TcdB is a critical therapeutic target for C. difficile infections.

Purpose of the Study:

  • To synthesize and evaluate novel compounds, including isofagomine analogues and acyclic mimics, for their ability to inhibit TcdB.
  • To investigate structure-activity relationships to identify modifications that enhance TcdB inhibition by utilizing UDP-binding energy.
  • To guide the development of future catalytic site inhibitors for TcdB.

Main Methods:

  • Synthesis of diverse compound classes, including isofagomine derivatives and acyclic mimics.
  • Utilized fluorescence and absorbance assays to assess the inhibition of TcdB's UDP-glucose hydrolysis.
  • Performed structure-activity relationship studies to understand the impact of molecular modifications on inhibitory activity.

Main Results:

  • Isofagomine derivatives showed high specificity for isofagomine itself, with limited improvement in accessing the UDP-binding site.
  • The synthesized compounds were evaluated for their ability to inhibit TcdB's GTD activity.
  • Assays confirmed the feasibility of assessing inhibition of TcdB's UDP-glucose hydrolysis.

Conclusions:

  • The study provides insights into the structure-activity relationships of isofagomine derivatives as TcdB inhibitors.
  • The findings guide the design of future scaffolds targeting the catalytic site of TcdB.
  • This research contributes to the development of novel therapeutics against C. difficile infections.