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

Zhang, Si Min; Rehling, Daniel; Throup, Adam; Landázuri, Natalia; Almlöf, Ingrid; Göttmann, Mona; Valerie, Nicholas C.K.; Borhade, Sanjay R.; Wakchaure, Prasad B.; Page, Brent D. G.; Desroses, Matthieu; Homan, Evert; Scobie, Martin; Rudd, Sean G.; Söderberg‐Nauclér, Cecilia; Stenmark, Pål; Helleday, Thomas

doi:10.1016/j.chembiol.2021.06.001

Cited by 13 publications

(24 citation statements)

References 36 publications

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“…As evidenced by a 5-fold higher production of Pi in the presence of PPase (Figure 3B), Molnupiravir-TP hydrolysis of the bond between the -and -phosphate groups appears to be preferred. In addition, NUDT15, previously shown to catalyze the hydrolysis of Ganciclovir-TP [27], was found to catalyze the hydrolysis of Molnupiravir-TP producing pyrophosphate, albeit with considerably lower efficiency compared to NUDT18, while MTH1 did not display any detectable activity with this substrate (Figure 3B). To investigate the activity of NUDT18 with these substrates in more detail we performed kinetic analyses of the NUDT18-catalyzed hydrolysis of Remdesivir-TP, Ribavirin-TP, Molnupiravir-TP and for comparison with 8-oxo-dGDP.…”

Section: Nudt18 Catalyzes the Hydrolysis Of Remdesivir-tp And Ribavir...mentioning

confidence: 89%

NUDT18 catalyzes the hydrolysis of active metabolites of the antivirals Remdesivir, Ribavirin and Molnupiravir

Scaletti

Homan

Stenmark

et al. 2021

Preprint

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Remdesivir (GS-5734) has gained considerable interest due to its activity against replication of SARS-CoV2. Remdesivir is a broad-spectrum antiviral prodrug that is hydrolyzed intracellularly and phosphorylated by cellular kinases to its active triphosphate form (Remdesivir-TP). Here we tested Remdesivir-TP as a substrate for a panel of human hydrolases and found that NUDIX hydrolase 18 (NUDT18) catalyzes the hydrolysis of Remdesivir-TP. NUDT18 is expressed in respiratory epithelial cells suggesting that NUDT18 may limit the antiviral efficacy of Remdesivir by decreasing the intracellular concentration of its active metabolite at its intended site of action. The kcat of NUDT18 for Remdesivir-TP was determined to 2.6 s-1 and the Km value was 156 μM, suggesting that NUDT18 catalyzed hydrolysis occurs in cells. In addition, we found that the triphosphate of the antiviral Ribavirin, with broad-spectrum activity against several RNA and DNA viruses, was hydrolyzed by NUDT18, albeit with a lower efficiency compared to Remdesivir-TP. NUDT18 activity was also tested with the triphosphates of the antivirals Sofosbuvir and Aciclovir for which low activity, in comparison to activities with Remdesivir-TP and Ribavirin-TP, was detected. These results suggest that NUDT18 can act as a cellular sanitizer and may influence the antiviral efficacy of Remdesivir and Ribavirin.

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Section: Nudt18 Catalyzes the Hydrolysis Of Remdesivir-tp And Ribavir...mentioning

confidence: 89%

NUDT18 catalyzes the hydrolysis of active metabolites of the antivirals Remdesivir, Ribavirin and Molnupiravir

Scaletti

Homan

Stenmark

et al. 2021

Preprint

Self Cite

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“…9 Recently, NUDT15 has been described to influence the in vitro metabolism of ganciclovir. 1,2 Triphosphate form of nucleoside analog drugs-including azathioprine and ganciclovir-mimicks natural nucleotides, incorporates into replicating DNA, prematurely terminates the chain, and thereby inhibits proliferation of human cell or DNA virus. NUDT15 hydrolyses active triphosphate form of the above two drugs to inactive monophosphate form (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…NUDT15 hydrolyses active triphosphate form of the above two drugs to inactive monophosphate form (Figure 2). 1,2,6,7 TPMT diverts azathioprine to inactive metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…

Recent "in vitro" studies describe nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) enzyme to be involved in the metabolism of ganciclovir. 1,2 We report severe leukopenia during therapy with valganciclovir in a recent kidney transplant recipient with NUDT15 genetic variation. This case report is the first to substantiate a theoretical postulate of increased valganciclovir toxicity with NUDT15 variation.

…”

mentioning

confidence: 91%

“…6,7 Two recent in vitro studies have shown that ganciclovir triphosphate-an active metabolite of ganciclovir-is also metabolized by cellular enzyme NUDT15. 1,2 Synthetic NUDT15 blockers are being developed to potentiate ganciclovir activity against drug-resistant CMV infection. In the laboratory setting, ganciclovir demonstrated increased anti-CMV activity, but also increased drug toxicity in NUDT15-deficient cells.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel risk factor for valganciclovir toxicity—NUDT15 genetic variant

Shingare

Dhope

Bahadur

2022

Transplant Infectious Dis

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Long‐read HiFi sequencing of NUDT15 : Phased full‐gene haplotyping and pharmacogenomic allele discovery

et al. 2022

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To determine the phase of NUDT15 sequence variants for more comprehensive star (*) allele diplotyping, we developed a novel long-read single-molecule real-time HiFi amplicon sequencing method. A 10.5 kb NUDT15 amplicon assay was validated using reference material positive controls and additional samples for specimen type and blinded accuracy assessment. Triplicate NUDT15 HiFi sequencing of two reference material samples had nonreference genotype concordances of >99.9%, indicating that the assay is robust. Notably, short-read genome sequencing of a subset of samples was unable to determine the phase of star (*) allele-defining NUDT15 variants, resulting in ambiguous diplotype results. In contrast, long-read HiFi sequencing phased all variants across the NUDT15 amplicons, including a *2/*9 diplotype that previously was characterized as *1/*2 in the 1000 Genomes Project v3 data set. Assay throughput was also tested using 8.5 kb amplicons from 100 Ashkenazi Jewish individuals, which identified a novel NUDT15 *1 suballele (c.−121G>A) and a rare likely deleterious coding variant (p.Pro129Arg). Both novel alleles were Sanger confirmed and assigned as *1.007 and *20, respectively, by the PharmVar Consortium. Taken together, NUDT15 HiFi amplicon sequencing is an innovative method for phased full-gene characterization and novel allele discovery, which could improve NUDT15 pharmacogenomic testing and subsequent phenotype prediction.

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

Cited by 13 publications

References 36 publications

NUDT18 catalyzes the hydrolysis of active metabolites of the antivirals Remdesivir, Ribavirin and Molnupiravir

NUDT18 catalyzes the hydrolysis of active metabolites of the antivirals Remdesivir, Ribavirin and Molnupiravir

Novel risk factor for valganciclovir toxicity—NUDT15 genetic variant

Long‐read HiFi sequencing of NUDT15 : Phased full‐gene haplotyping and pharmacogenomic allele discovery

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