The Enzyme-Free Release of Nucleotides from Phosphoramidates Depends Strongly on the Amino Acid.
Adenosine Monophosphate
/ analogs & derivatives
Alanine
/ analogs & derivatives
Amides
/ chemistry
Amino Acids
/ chemistry
Antiviral Agents
/ chemistry
COVID-19
/ pathology
Catalytic Domain
Crystallography, X-Ray
Half-Life
Hydrogen-Ion Concentration
Hydrolysis
Kinetics
Molecular Dynamics Simulation
Nucleotides
/ chemistry
Phosphoric Acids
/ chemistry
Ribonuclease, Pancreatic
/ chemistry
SARS-CoV-2
/ drug effects
COVID-19 Drug Treatment
SARS-CoV-2
antivirals
nucleotides
phosphoramidates
prodrugs
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
02 11 2020
02 11 2020
Historique:
received:
19
06
2020
revised:
04
08
2020
pubmed:
7
8
2020
medline:
23
12
2020
entrez:
7
8
2020
Statut:
ppublish
Résumé
Phosphoramidates composed of an amino acid and a nucleotide analogue are critical metabolites of prodrugs, such as remdesivir. Hydrolysis of the phosphoramidate liberates the nucleotide, which 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.
Identifiants
pubmed: 32757352
doi: 10.1002/anie.202008665
pmc: PMC7436718
doi:
Substances chimiques
Amides
0
Amino Acids
0
Antiviral Agents
0
Nucleotides
0
Phosphoric Acids
0
remdesivir
3QKI37EEHE
Adenosine Monophosphate
415SHH325A
phosphoramidic acid
9Q189608GB
Ribonuclease, Pancreatic
EC 3.1.27.5
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
20154-20160Subventions
Organisme : Volkswagen Foundation
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : project ID 364653263 - TRR 235
Pays : International
Informations de copyright
© 2020 The Authors. Published by Wiley-VCH GmbH.
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