Comparative Study of Adenosine Analogs as Inhibitors of Protein Arginine Methyltransferases and a Clostridioides difficile- Specific DNA Adenine Methyltransferase.

Autor: Zhou J; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States., Deng Y; Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States., Iyamu ID; Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States., Horton JR; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States., Yu D; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States., Hajian T; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada., Vedadi M; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.; Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada., Rotili D; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy., Mai A; Department of Drug Chemistry and Technologies, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy., Blumenthal RM; 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., Zhang X; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States., Huang R; Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States., Cheng X; Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, United States.
Jazyk: angličtina
Zdroj: ACS chemical biology [ACS Chem Biol] 2023 Apr 21; Vol. 18 (4), pp. 734-745. Date of Electronic Publication: 2023 Feb 22.
DOI: 10.1021/acschembio.3c00035
Abstrakt: S -Adenosyl-l-methionine (SAM) analogs are adaptable tools for studying and therapeutically inhibiting SAM-dependent methyltransferases (MTases). Some MTases play significant roles in host-pathogen interactions, one of which is Clostridioides difficile -specific DNA adenine MTase (CamA). CamA is needed for efficient sporulation and alters persistence in the colon. To discover potent and selective CamA inhibitors, we explored modifications of the solvent-exposed edge of the SAM adenosine moiety. Starting from the two parental compounds ( 6e and 7 ), we designed an adenosine analog ( 11a ) carrying a 3-phenylpropyl moiety at the adenine N6-amino group, and a 3-(cyclohexylmethyl guanidine)-ethyl moiety at the sulfur atom off the ribose ring. Compound 11a (IC 50 = 0.15 μM) is 10× and 5× more potent against CamA than 6e and 7 , respectively. The structure of the CamA-DNA-inhibitor complex revealed that 11a adopts a U-shaped conformation, with the two branches folded toward each other, and the aliphatic and aromatic rings at the two ends interacting with one another. 11a occupies the entire hydrophobic surface (apparently unique to CamA) next to the adenosine binding site. Our work presents a hybrid knowledge-based and fragment-based approach to generating CamA inhibitors that would be chemical agents to examine the mechanism(s) of action and therapeutic potentials of CamA in C. difficile infection.
Databáze: MEDLINE
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