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NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir

Zhang, Si Min ; Rehling, Daniel ; Jemth, Ann-Sofie ; Throup, Adam ; Landázuri, Natalia ; Almlöf, Ingrid ; Göttmann, Mona ; Valerie, Nicholas C K ; Borhade, Sanjay R and Wakchaure, Prasad , et al. (2021) In Cell Chemical Biology 28(12). p.6-1702
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cell Chemical Biology
volume
28
issue
12
pages
6 - 1702
publisher
Elsevier
external identifiers
  • pmid:34192523
  • scopus:85120967506
ISSN
2451-9448
DOI
10.1016/j.chembiol.2021.06.001
language
English
LU publication?
yes
id
000b115f-b385-4e21-a3f2-9ed83fbd4592
date added to LUP
2021-07-05 10:19:58
date last changed
2024-06-15 13:12:42
@article{000b115f-b385-4e21-a3f2-9ed83fbd4592,
  abstract     = {{<p>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.</p>}},
  author       = {{Zhang, Si Min and Rehling, Daniel and Jemth, Ann-Sofie and Throup, Adam and Landázuri, Natalia and Almlöf, Ingrid and Göttmann, Mona and Valerie, Nicholas C K and Borhade, Sanjay R and Wakchaure, Prasad and Page, Brent D G and Desroses, Matthieu and Homan, Evert J and Scobie, Martin and Rudd, Sean G and Berglund, Ulrika Warpman and Söderberg-Nauclér, Cecilia and Stenmark, Pål and Helleday, Thomas}},
  issn         = {{2451-9448}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{12}},
  pages        = {{6--1702}},
  publisher    = {{Elsevier}},
  series       = {{Cell Chemical Biology}},
  title        = {{NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir}},
  url          = {{http://dx.doi.org/10.1016/j.chembiol.2021.06.001}},
  doi          = {{10.1016/j.chembiol.2021.06.001}},
  volume       = {{28}},
  year         = {{2021}},
}