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

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, Yoshiko Atsuta, Lei Yang, Wenjian Yang, Paul G. Thomas, Pål Stenmark (), Motohiro Kato () and Jun J. Yang ()
Additional contact information
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
Motohiro Kato: National Center for Child Health and Development
Jun J. Yang: St. Jude Children’s Research Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24509-7

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