Key result
NUDT18 hydrolyzes active metabolites of remdesivir, ribavirin, and molnupiravir, potentially limiting their antiviral efficacy.
Why the study?
Cellular hydrolysis of the active triphosphate forms of Remdesivir and Molnupiravir could decrease their antiviral efficacy against SARS-CoV-2, but the responsible enzymes were not fully identified.
Effect estimate: kcat 2.6 s-1, Km 156 µM
NUDT18 acts as a cellular sanitizer that hydrolyzes the active metabolites of Remdesivir and Molnupiravir, potentially limiting their antiviral efficacy against SARS-CoV-2.
NUDT18 may limit remdesivir and molnupiravir activity; hypothesis-generating for NUDT18 inhibition to enhance antiviral efficacy.
Remdesivir and Molnupiravir have gained considerable interest due to their activity against SARS-CoV-2. Cellular hydrolysis of their active triphosphate forms, Remdesivir-TP and Molnupiravir-TP, would decrease drug efficiency. We therefore tested Remdesivir-TP as a substrate against a panel of human hydrolases and found that NUDT18 catalyzes the hydrolysis of Remdesivir-TP. The k cat value of NUDT18 for Remdesivir-TP was determined to 2.6 s -1 and the K m value was 156 μM, suggesting that NUDT18 catalyzed hydrolysis of Remdesivir-TP occurs in cells. We demonstrate that the triphosphates of the antivirals Ribavirin and Molnupiravir are hydrolyzed by NUDT18, albeit with a lower efficiency compared to Remdesivir-TP. NUDT18 also hydrolyses the triphosphates of Sofosbuvir and Aciclovir although with significantly lower activity. These results suggest that NUDT18 can act as a cellular sanitizer of modified nucleotides and may influence the antiviral efficacy of Remdesivir, Molnupiravir and Ribavirin. NUDT18 is expressed in respiratory epithelial cells and may limit the antiviral efficacy of Remdesivir and Molnupiravir against SARS-CoV2 replication by decreasing the intracellular concentration of their active metabolites at their intended site of action.
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Jemth et al. (2021) studied Viral infection. NUDT18 vs. Other NUDIX hydrolases was evaluated on Hydrolysis of Remdesivir-TP (kcat 2.6 s-1, Km 156 µM). NUDT18 catalyzes the hydrolysis of the active metabolite Remdesivir-TP (kcat 2.6 s-1, Km 156 µM), as well as Ribavirin-TP and Molnupiravir-TP, potentially limiting their antiviral efficacy.
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