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

Zhou J, Horton JR, Menna M, Fiorentino F, Ren R, Yu D, Hajian T, Vedadi M, Mazzoccanti G, Ciogli A, Weinhold E, Hüben M, Blumenthal RM, Zhang X, Mai A, Rotili D, Cheng X
J Med Chem (2022)
Related entries: 8cxt, 8cxu, 8cxv, 8cxw, 8cxx, 8cxy, 8cxz, 8cy0, 8cy1, 8cy2, 8cy3, 8cy4, 8cy5

Cited: 3 times
EuropePMC logo PMID: 36581322

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

Articles - 8cxs mentioned but not cited (1)

  1. Systematic Design of Adenosine Analogs as Inhibitors of a Clostridioides difficile-Specific DNA Adenine Methyltransferase Required for Normal Sporulation and Persistence. Zhou J, Horton JR, Menna M, Fiorentino F, Ren R, Yu D, Hajian T, Vedadi M, Mazzoccanti G, Ciogli A, Weinhold E, Hüben M, Blumenthal RM, Zhang X, Mai A, Rotili D, Cheng X. J Med Chem 66 934-950 (2023)


Articles citing this publication (2)

  1. Biochemical and structural characterization of the first-discovered metazoan DNA cytosine-N4 methyltransferase from the bdelloid rotifer Adineta vaga. Zhou J, Horton JR, Kaur G, Chen Q, Li X, Mendoza F, Wu T, Blumenthal RM, Zhang X, Cheng X. J Biol Chem 299 105017 (2023)
  2. Comparative Study of Adenosine Analogs as Inhibitors of Protein Arginine Methyltransferases and a Clostridioides difficile-Specific DNA Adenine Methyltransferase. Zhou J, Deng Y, Iyamu ID, Horton JR, Yu D, Hajian T, Vedadi M, Rotili D, Mai A, Blumenthal RM, Zhang X, Huang R, Cheng X. ACS Chem Biol 18 734-745 (2023)


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