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Nudix hydrolase 18 catalyzes the hydrolysis of active triphosphate metabolites of the antivirals remdesivir, ribavirin, and molnupiravir.
Jemth, Ann-Sofie; Scaletti, Emma Rose; Homan, Evert; Stenmark, Pål; Helleday, Thomas; Michel, Maurice.
  • Jemth AS; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. Electronic address: ann-sofie.jemth@ki.se.
  • Scaletti ER; Department of Biochemistry & Biophysics, Stockholm University, Stockholm, Sweden.
  • Homan E; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
  • Stenmark P; Department of Biochemistry & Biophysics, Stockholm University, Stockholm, Sweden.
  • Helleday T; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden; Weston Park Cancer Centre, Department of Oncology & Metabolism, Medical School, University of Sheffield, Sheffield, United Kingdom.
  • Michel M; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden. Electronic address: maurice.michel@ki.se.
J Biol Chem ; 298(8): 102169, 2022 08.
Article in English | MEDLINE | ID: covidwho-1895142
ABSTRACT
Remdesivir and molnupiravir have gained considerable interest because of their demonstrated activity against SARS-CoV-2. These antivirals are converted intracellularly to their active triphosphate forms remdesivir-TP and molnupiravir-TP. Cellular hydrolysis of these active metabolites would consequently decrease the efficiency of these drugs; however, whether endogenous enzymes that can catalyze this hydrolysis exist is unknown. Here, we tested remdesivir-TP as a substrate against a panel of human hydrolases and found that only Nudix hydrolase (NUDT) 18 catalyzed the hydrolysis of remdesivir-TP with notable activity. The kcat/Km value of NUDT18 for remdesivir-TP was determined to be 17,700 s-1M-1, suggesting that NUDT18-catalyzed hydrolysis of remdesivir-TP may occur in cells. Moreover, we demonstrate that the triphosphates of the antivirals ribavirin and molnupiravir are also hydrolyzed by NUDT18, albeit with lower efficiency than Remdesivir-TP. Low activity was also observed with the triphosphate forms of sofosbuvir and aciclovir. This is the first report showing that NUDT18 hydrolyzes triphosphates of nucleoside analogs of exogenous origin, suggesting that NUDT18 can act as a cellular sanitizer of modified nucleotides and may influence the antiviral efficacy of remdesivir, molnupiravir, and ribavirin. As NUDT18 is expressed in respiratory epithelial cells, it may limit the antiviral efficacy of remdesivir and molnupiravir against SARS-CoV-2 replication by decreasing the intracellular concentration of their active metabolites at their intended site of action.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / COVID-19 Drug Treatment Limits: Humans Language: English Journal: J Biol Chem Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / COVID-19 Drug Treatment Limits: Humans Language: English Journal: J Biol Chem Year: 2022 Document Type: Article