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000169400 0247_ $$2doi$$a10.1016/j.chembiol.2021.06.001
000169400 0247_ $$2pmid$$apmid:34192523
000169400 0247_ $$2ISSN$$a2451-9448
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000169400 037__ $$aDKFZ-2021-01474
000169400 041__ $$aEnglish
000169400 082__ $$a570
000169400 1001_ $$aZhang, Si Min$$b0
000169400 245__ $$aNUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir.
000169400 260__ $$aAmsterdam$$bElsevier$$c2021
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000169400 500__ $$a2021 Dec 16;28(12):1693-1702.e6
000169400 520__ $$aGanciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV.
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000169400 650_7 $$2Other$$aNUDT15
000169400 650_7 $$2Other$$aNudix hydrolase
000169400 650_7 $$2Other$$aTH8321
000169400 650_7 $$2Other$$aantiherpes
000169400 650_7 $$2Other$$acytomegalovirus
000169400 650_7 $$2Other$$aganciclovir
000169400 650_7 $$2Other$$ahigh-throughput infectivity assay
000169400 650_7 $$2Other$$anucleoside analog drug
000169400 650_7 $$2Other$$asmall-molecule inhibitor
000169400 7001_ $$aRehling, Daniel$$b1
000169400 7001_ $$aJemth, Ann-Sofie$$b2
000169400 7001_ $$aThroup, Adam$$b3
000169400 7001_ $$aLandázuri, Natalia$$b4
000169400 7001_ $$aAlmlöf, Ingrid$$b5
000169400 7001_ $$0P:(DE-He78)442ee8f54d846d943023a916889feb8e$$aGöttmann, Mona$$b6$$udkfz
000169400 7001_ $$aValerie, Nicholas C K$$b7
000169400 7001_ $$aBorhade, Sanjay R$$b8
000169400 7001_ $$aWakchaure, Prasad$$b9
000169400 7001_ $$aPage, Brent D G$$b10
000169400 7001_ $$aDesroses, Matthieu$$b11
000169400 7001_ $$aHoman, Evert J$$b12
000169400 7001_ $$aScobie, Martin$$b13
000169400 7001_ $$aRudd, Sean G$$b14
000169400 7001_ $$aBerglund, Ulrika Warpman$$b15
000169400 7001_ $$aSöderberg-Nauclér, Cecilia$$b16
000169400 7001_ $$aStenmark, Pål$$b17
000169400 7001_ $$aHelleday, Thomas$$b18
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