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

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 pat...

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Autores principales: Nishii, Rina, Mizuno, Takanori, Rehling, Daniel, Smith, Colton, Clark, Brandi L., Zhao, Xujie, Brown, Scott A., Smart, Brandon, Moriyama, Takaya, Yamada, Yuji, Ichinohe, Tatsuo, Onizuka, Makoto, Atsuta, Yoshiko, Yang, Lei, Yang, Wenjian, Thomas, Paul G., Stenmark, Pål, Kato, Motohiro, Yang, Jun J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263746/
https://www.ncbi.nlm.nih.gov/pubmed/34234136
http://dx.doi.org/10.1038/s41467-021-24509-7
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author Nishii, Rina
Mizuno, Takanori
Rehling, Daniel
Smith, Colton
Clark, Brandi L.
Zhao, Xujie
Brown, Scott A.
Smart, Brandon
Moriyama, Takaya
Yamada, Yuji
Ichinohe, Tatsuo
Onizuka, Makoto
Atsuta, Yoshiko
Yang, Lei
Yang, Wenjian
Thomas, Paul G.
Stenmark, Pål
Kato, Motohiro
Yang, Jun J.
author_facet Nishii, Rina
Mizuno, Takanori
Rehling, Daniel
Smith, Colton
Clark, Brandi L.
Zhao, Xujie
Brown, Scott A.
Smart, Brandon
Moriyama, Takaya
Yamada, Yuji
Ichinohe, Tatsuo
Onizuka, Makoto
Atsuta, Yoshiko
Yang, Lei
Yang, Wenjian
Thomas, Paul G.
Stenmark, Pål
Kato, Motohiro
Yang, Jun J.
author_sort Nishii, Rina
collection PubMed
description 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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spelling pubmed-82637462021-07-23 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 Yamada, Yuji Ichinohe, Tatsuo Onizuka, Makoto Atsuta, Yoshiko Yang, Lei Yang, Wenjian Thomas, Paul G. Stenmark, Pål Kato, Motohiro Yang, Jun J. Nat Commun Article 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. Nature Publishing Group UK 2021-07-07 /pmc/articles/PMC8263746/ /pubmed/34234136 http://dx.doi.org/10.1038/s41467-021-24509-7 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Nishii, Rina
Mizuno, Takanori
Rehling, Daniel
Smith, Colton
Clark, Brandi L.
Zhao, Xujie
Brown, Scott A.
Smart, Brandon
Moriyama, Takaya
Yamada, Yuji
Ichinohe, Tatsuo
Onizuka, Makoto
Atsuta, Yoshiko
Yang, Lei
Yang, Wenjian
Thomas, Paul G.
Stenmark, Pål
Kato, Motohiro
Yang, Jun J.
NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
title NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
title_full NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
title_fullStr NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
title_full_unstemmed NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
title_short NUDT15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
title_sort nudt15 polymorphism influences the metabolism and therapeutic effects of acyclovir and ganciclovir
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263746/
https://www.ncbi.nlm.nih.gov/pubmed/34234136
http://dx.doi.org/10.1038/s41467-021-24509-7
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