Discovery of a Novel Inhibitor of Human Purine Nucleoside Phosphorylase by a Simple Hydrophilic Interaction Liquid Chromatography Enzymatic Assay.
Antineoplastic Agents
/ analysis
Catalytic Domain
Cell Line, Tumor
Chromatography, Liquid
/ methods
Drug Screening Assays, Antitumor
Enzyme Assays
/ methods
Enzyme Inhibitors
/ analysis
Humans
Inosine
/ analogs & derivatives
Molecular Docking Simulation
Protein Binding
Purine-Nucleoside Phosphorylase
/ antagonists & inhibitors
Small Molecule Libraries
/ analysis
PNP inhibitors
antitumour activity
drug discovery
enzymatic assay
screening
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
20 04 2021
20 04 2021
Historique:
received:
09
11
2020
pubmed:
7
1
2021
medline:
12
1
2022
entrez:
6
1
2021
Statut:
ppublish
Résumé
Human purine nucleoside phosphorylase (HsPNP) belongs to the purine salvage pathway of nucleic acids. Genetic deficiency of this enzyme triggers apoptosis of activated T-cells due to the accumulation of deoxyguanosine triphosphate (dGTP). Therefore, potential chemotherapeutic applications of human PNP inhibitors include the treatment of T-cell leukemia, autoimmune diseases and transplant tissue rejection. In this report, we present the discovery of novel HsPNP inhibitors by coupling experimental and computational tools. A simple, inexpensive, direct and non-radioactive enzymatic assay coupled to hydrophilic interaction liquid chromatography and UV detection (LC-UV using HILIC as elution mode) was developed for screening HsPNP inhibitors. Enzymatic activity was assessed by monitoring the phosphorolysis of inosine (Ino) to hypoxanthine (Hpx) by LC-UV. A small library of 6- and 8-substituted nucleosides was synthesized and screened. The inhibition potency of the most promising compound, 8-aminoinosine (4), was quantified through K
Identifiants
pubmed: 33405358
doi: 10.1002/cmdc.202000874
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Small Molecule Libraries
0
Inosine
5A614L51CT
Purine-Nucleoside Phosphorylase
EC 2.4.2.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1325-1334Subventions
Organisme : Conselho Nacional de Desenvolvimento Cientifico e Tecnológico
Organisme : Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
ID : E-26/202.909/2019
Informations de copyright
© 2021 Wiley-VCH GmbH.
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