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Impact of remdesivir modifications on human HINT1 binding - A structural and functional study in the remdesivir
Aurélie Chazot1, Claire Zimberger1, Ioannis Fotopoulos1
1Aix Marseille Université, CNRS, AFMB, UMR 7257 Marseille, France.
Abstract:
Remdesivir is an antiviral ProTide-type nucleotide analog, which is activated into its 5'-triphosphate form by several cellular enzymes. The human histidine triad nucleotide-binding protein 1 (hHINT1) hydrolyzes the P-N bond to release the 5'-monophosphate. The nucleotide chemical structure consequently impacts the activation pathway efficacy. We report crystal structures of human HINT1 in complex with either the nucleoside GS-441524 or the monophosphate nucleoside GS-441524-MP-both metabolites of remdesivir at 1.30 Å and 1.58 Å resolution, respectively. Together with enzymatic data, these results disclose the main structural determinants governing activity, namely the steric hindrance of the phosphoramidate moiety as well as ribose modifications altering interactions with Asp43.
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