2. Academic Validation
  3. Structure-Activity Relationship of Pseudouridimycin Focusing on the Improvement of Chemical Stability

Structure-Activity Relationship of Pseudouridimycin Focusing on the Improvement of Chemical Stability

  • J Med Chem. 2025 Aug 14;68(15):15461-15482. doi: 10.1021/acs.jmedchem.5c00052.
Ryotaro Okawa 1,  Irina Artsimovitch 2,  Akira Katsuyama 1 3,  Toyotaka Sato 4,  Courtney C Aldrich 5,  Satoshi Ichikawa 1 3
Affiliations

Affiliations

  • 1 Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
  • 2 Department of Microbiology and Center for RNA Biology, The Ohio State University, Columbus, Ohio 43210, United States.
  • 3 Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
  • 4 Laboratory of Veterinary Hygiene, School/Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan.
  • 5 Department of Medicinal Chemistry, Minnesota University, Minneappolis, Minnesota 55455, United States.
PMID: 40697156 DOI: 10.1021/acs.jmedchem.5c00052
Abstract

In recent years, the spread of drug-resistant Bacterial infections has driven a critical demand for new antimicrobial agents with novel mechanisms of action. Pseudouridimycin (PUM) is a nucleoside Antibiotic that inhibits Bacterial DNA-dependent RNA polymerase (RNAP) by binding in the conserved active site that is distinct from the mutable allosteric sites targeted by the clinically approved rifamycin-class of Antibiotics. However, translational development of PUM is compromised by its poor intrinsic chemical stability and competitive modality of inhibition with respect to UTP, which will require further augmentation of binding affinity. We have conducted structure-activity relationship (SAR) studies on PUM by approaching these two problems through the rational design of analogs based on the known PUM·RNAP X-ray cocrystal structure and through elucidation of the decomposition mechanisms.

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