About: The Enzyme‐Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid

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An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	The Enzyme‐Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid
Creator	Egli, Martin Jovanovic, Dejana Pallan, Pradeep Pallan, S Richert, Clemens Tremmel, Peter
Source	PMC
abstract	Phosphoramidates composed of an amino acid and a nucleotide analog are critical metabolites of prodrugs, such as remdesivir. Hydrolysis of the phosphoramidate liberates the nucleotide that can then be phosphorylated to become the pharmacologically active triphosphate. Enzymatic hydrolysis has been demonstrated, but a spontaneous chemical process may also occur. We measured the rate of enzyme‐free hydrolysis for 17 phosphoramidates of ribonucleotides with amino acids or related compounds at pH 7.5. Phosphoramidates of proline hydrolyzed fast, with a half‐life time as short as 2.4 h for Pro‐AMP in ethylimidazole‐containing buffer at 37 °C; 45‐fold faster than Ala‐AMP and 120‐fold faster than Phe‐AMP. Crystal structures of Gly‐AMP, Pro‐AMP, βPro‐AMP and Phe‐AMP bound to RNase A as crystallization chaperone showed how well the carboxylate is poised to attack the phosphoramidate, helping to explain this reactivity. Our results are significant for the design of new antiviral prodrugs.
has issue date	2020-08-05(xsd:dateTime)
bibo:doi	10.1002/anie.202008665
bibo:pmid	32757352
has license	no-cc
sha1sum (hex)	9d0d65fd82e6cb8f0e69e8fd8a949c04c81e40df
schema:url	https://doi.org/10.1002/anie.202008665
resource representing a document's title	The Enzyme‐Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid
has PubMed Central identifier	PMC7436718
has PubMed identifier	32757352
schema:publication	Angew Chem Int Ed Engl
resource representing a document's body	covid:9d0d65fd82e6cb8f0e69e8fd8a949c04c81e40df#body_text
is schema:about of	named entity 'antiviral' named entity 'Nucleotides' named entity 'TRIPHOSPHATE' named entity 'SHORT' named entity 'PH 7' named entity 'INTERNATIONAL' named entity 'faster' named entity 'RNase A' named entity 'reactivity' named entity 'half-life' named entity 'fold' named entity 'Our' named entity 'phosphorylated' named entity 'demonstrated' named entity 'faster' named entity 'composed' named entity '37 °C' named entity 'Phosphoramidates' named entity 'Crystal structures' named entity 'Hydrolysis' named entity 'phosphoramidate' named entity 'Enzymatic hydrolysis' named entity 'phosphoramidate' named entity 'Amino Acid' named entity 'Enzyme' named entity 'Enzyme' named entity 'Phosphoramidates' named entity 'amino acids' named entity 'lipophilic' named entity 'kinetics' named entity 'nucleoside' named entity 'alanine' named entity 'nucleophilic' named entity 'methanol' named entity 'tRNA' named entity 'phosphates' named entity 'labile' named entity 'histidine' named entity 'nucleotide' named entity 'Gly' named entity 'amino acid' named entity 'electron density' named entity 'cell membranes' named entity 'crystallization' named entity 'protein' named entity 'rate limiting' named entity 'RNase' named entity 'acetic acid' named entity 'hepatocyte' named entity 'phosphoramidates' named entity 'ester' named entity 'HIV' named entity 'bond cleavage' named entity 'Preclinical' named entity 'active sites' named entity 'animal models' named entity '7.5' named entity 'ribonucleotides' named entity 'Phe' named entity 'nucleotide' named entity 'Phe' named entity 'polymerase' named entity 'asymmetric unit' named entity 'Lys' named entity 'Viral' named entity 'nucleotide' named entity 'phosphoramidate' named entity 'emergency use authorization' named entity 'plasma' named entity 'RNase' named entity 'aspartic acid' named entity 'sterically' named entity 'sofosbuvir' named entity 'hydrolyze' named entity 'enzyme' named entity 'nucleotide'

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