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@ARTICLE{Zhang:169400,
      author       = {S. M. Zhang and D. Rehling and A.-S. Jemth and A. Throup
                      and N. Landázuri and I. Almlöf and M. Göttmann$^*$ and N.
                      C. K. Valerie and S. R. Borhade and P. Wakchaure and B. D.
                      G. Page and M. Desroses and E. J. Homan and M. Scobie and S.
                      G. Rudd and U. W. Berglund and C. Söderberg-Nauclér and P.
                      Stenmark and T. Helleday},
      title        = {{NUDT}15-mediated hydrolysis limits the efficacy of
                      anti-{HCMV} drug ganciclovir.},
      journal      = {Cell chemical biology},
      volume       = {28},
      number       = {12},
      issn         = {2451-9456},
      address      = {Amsterdam},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2021-01474},
      pages        = {1693-1702.e6},
      year         = {2021},
      note         = {2021 Dec 16;28(12):1693-1702.e6},
      abstract     = {Ganciclovir (GCV) is the first-line therapy against human
                      cytomegalovirus (HCMV), a widespread infection that is
                      particularly dangerous for immunodeficient individuals.
                      Closely resembling deoxyguanosine triphosphate, the
                      tri-phosphorylated metabolite of GCV (GCV-TP) is
                      preferentially incorporated by the viral DNA polymerase,
                      thereby terminating chain extension and, eventually, viral
                      replication. However, the treatment outcome of GCV varies
                      greatly among individuals, therefore warranting better
                      understanding of its metabolism. Here we show that NUDT15, a
                      Nudix hydrolase known to metabolize thiopurine
                      triphosphates, can similarly hydrolyze GCV-TP through
                      biochemical studies and co-crystallization of the
                      NUDT15/GCV-TP complex. More critically, GCV efficacy was
                      potentiated in HCMV-infected cells following NUDT15
                      depletion by RNAi or inhibition by an in-house-developed,
                      nanomolar NUDT15 inhibitor, TH8321, suggesting that
                      pharmacological targeting of NUDT15 is a possible avenue to
                      improve existing anti-HCMV regimens. Collectively, the data
                      further implicate NUDT15 as a broad-spectrum metabolic
                      regulator of nucleoside analog therapeutics, such as
                      thiopurines and GCV.},
      keywords     = {NUDT15 (Other) / Nudix hydrolase (Other) / TH8321 (Other) /
                      antiherpes (Other) / cytomegalovirus (Other) / ganciclovir
                      (Other) / high-throughput infectivity assay (Other) /
                      nucleoside analog drug (Other) / small-molecule inhibitor
                      (Other)},
      cin          = {B067},
      ddc          = {570},
      cid          = {I:(DE-He78)B067-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34192523},
      doi          = {10.1016/j.chembiol.2021.06.001},
      url          = {https://inrepo02.dkfz.de/record/169400},
}