2. Academic Validation
  3. Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile- Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence

Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile- Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence

  • J Med Chem. 2023 Jan 12;66(1):934-950. doi: 10.1021/acs.jmedchem.2c01789.
Jujun Zhou 1,  John R Horton 1,  Martina Menna 2,  Francesco Fiorentino 2,  Ren Ren 1,  Dan Yu 1,  Taraneh Hajian 3,  Masoud Vedadi 3 4,  Giulia Mazzoccanti 2,  Alessia Ciogli 2,  Elmar Weinhold 5,  Michael Hüben 5,  Robert M Blumenthal 6,  Xing Zhang 1,  Antonello Mai 2 7,  Dante Rotili 2,  Xiaodong Cheng 1
Affiliations

Affiliations

  • 1 Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
  • 2 Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
  • 3 Structural Genomics Consortium, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 4 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 5 Institute of Organic Chemistry, RWTH Aachen University, D-52056 Aachen, Germany.
  • 6 Department of Medical Microbiology and Immunology, and Program in Bioinformatics, The University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States.
  • 7 Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
PMID: 36581322 DOI: 10.1021/acs.jmedchem.2c01789
Abstract

Antivirulence agents targeting endospore-transmitted Clostridioides difficile infections are urgently needed. C. difficile-specific DNA adenine methyltransferase (CamA) is required for efficient sporulation and affects persistence in the colon. The active site of CamA is conserved and closely resembles those of hundreds of related S-adenosyl-l-methionine (SAM)-dependent methyltransferases, which makes the design of selective inhibitors more challenging. We explored the solvent-exposed edge of the SAM adenosine moiety and systematically designed 42 analogs of adenosine carrying substituents at the C6-amino group (N6) of adenosine. We compare the inhibitory properties and binding affinity of these diverse compounds and present the crystal structures of CamA in complex with 14 of them in the presence of substrate DNA. The most potent of these inhibitors, compound 39 (IC50 ∼ 0.4 μM and KD ∼ 0.2 μM), is selective for CamA against closely related Bacterial and mammalian DNA and RNA adenine methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors.

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