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NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir

Author

Listed:
  • Rina Nishii

    (St. Jude Children’s Research Hospital)

  • Takanori Mizuno

    (National Center for Child Health and Development)

  • Daniel Rehling

    (Stockholm University)

  • Colton Smith

    (St. Jude Children’s Research Hospital)

  • Brandi L. Clark

    (St. Jude Children’s Research Hospital)

  • Xujie Zhao

    (St. Jude Children’s Research Hospital)

  • Scott A. Brown

    (St. Jude Children’s Research Hospital)

  • Brandon Smart

    (St. Jude Children’s Research Hospital)

  • Takaya Moriyama

    (St. Jude Children’s Research Hospital)

  • Yuji Yamada

    (National Center for Child Health and Development)

  • Tatsuo Ichinohe

    (Hiroshima University)

  • Makoto Onizuka

    (Tokai University School of Medicine)

  • Yoshiko Atsuta

    (Japanese Data Center for Hematopoietic Cell Transplantation)

  • Lei Yang

    (St. Jude Children’s Research Hospital)

  • Wenjian Yang

    (St. Jude Children’s Research Hospital)

  • Paul G. Thomas

    (St. Jude Children’s Research Hospital)

  • Pål Stenmark

    (Stockholm University
    Lund University)

  • Motohiro Kato

    (National Center for Child Health and Development)

  • Jun J. Yang

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

Abstract

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.

Suggested Citation

  • Rina Nishii & Takanori Mizuno & Daniel Rehling & Colton Smith & Brandi L. Clark & Xujie Zhao & Scott A. Brown & Brandon Smart & Takaya Moriyama & Yuji Yamada & Tatsuo Ichinohe & Makoto Onizuka & Yoshi, 2021. "NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24509-7
    DOI: 10.1038/s41467-021-24509-7
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