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

Nishii, Rina ; Mizuno, Takanori ; Rehling, Daniel ; Smith, Colton ; Clark, Brandi L ; Zhao, Xujie ; Brown, Scott A ; Smart, Brandon ; Moriyama, Takaya and Yamada, Yuji , et al. (2021) In Nature Communications 12(1).
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 =... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
12
issue
1
article number
4181
publisher
Nature Publishing Group
external identifiers
  • pmid:34234136
  • scopus:85109719453
ISSN
2041-1723
DOI
10.1038/s41467-021-24509-7
language
English
LU publication?
yes
id
7f683226-03c1-4890-86cb-e642e220547f
date added to LUP
2021-07-18 16:29:40
date last changed
2024-07-27 17:58:04
@article{7f683226-03c1-4890-86cb-e642e220547f,
  abstract     = {{<p>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.</p>}},
  author       = {{Nishii, Rina and Mizuno, Takanori and Rehling, Daniel and Smith, Colton and Clark, Brandi L and Zhao, Xujie and Brown, Scott A and Smart, Brandon and Moriyama, Takaya and Yamada, Yuji and Ichinohe, Tatsuo and Onizuka, Makoto and Atsuta, Yoshiko and Yang, Lei and Yang, Wenjian and Thomas, Paul G and Stenmark, Pål and Kato, Motohiro and Yang, Jun J}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-24509-7}},
  doi          = {{10.1038/s41467-021-24509-7}},
  volume       = {{12}},
  year         = {{2021}},
}