Home > Publications database > NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir. > print

001     169400
005     20240229133650.0
024 7 _ |a 10.1016/j.chembiol.2021.06.001
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024 7 _ |a pmid:34192523
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024 7 _ |a 2451-9448
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024 7 _ |a 2451-9456
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037 _ _ |a DKFZ-2021-01474
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Zhang, Si Min
|b 0
245 _ _ |a NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir.
260 _ _ |a Amsterdam
|c 2021
|b Elsevier
336 7 _ |a article
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500 _ _ |a 2021 Dec 16;28(12):1693-1702.e6
520 _ _ |a 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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650 _ 7 |a NUDT15
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650 _ 7 |a Nudix hydrolase
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650 _ 7 |a TH8321
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650 _ 7 |a antiherpes
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650 _ 7 |a cytomegalovirus
|2 Other
650 _ 7 |a ganciclovir
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650 _ 7 |a high-throughput infectivity assay
|2 Other
650 _ 7 |a nucleoside analog drug
|2 Other
650 _ 7 |a small-molecule inhibitor
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700 1 _ |a Rehling, Daniel
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700 1 _ |a Jemth, Ann-Sofie
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700 1 _ |a Throup, Adam
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700 1 _ |a Landázuri, Natalia
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700 1 _ |a Almlöf, Ingrid
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700 1 _ |a Göttmann, Mona
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700 1 _ |a Valerie, Nicholas C K
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700 1 _ |a Borhade, Sanjay R
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700 1 _ |a Wakchaure, Prasad
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700 1 _ |a Page, Brent D G
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700 1 _ |a Desroses, Matthieu
|b 11
700 1 _ |a Homan, Evert J
|b 12
700 1 _ |a Scobie, Martin
|b 13
700 1 _ |a Rudd, Sean G
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700 1 _ |a Berglund, Ulrika Warpman
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700 1 _ |a Söderberg-Nauclér, Cecilia
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700 1 _ |a Stenmark, Pål
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700 1 _ |a Helleday, Thomas
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773 _ _ |a 10.1016/j.chembiol.2021.06.001
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