Interactions of 2,6-substituted purines with purine nucleoside phosphorylase from Helicobacter pylori in solution and in the crystal, and the effects of these compounds on cell cultures of this bacterium

Helicobacter pylori represents a global health threat with around 50% of the world population infected. Due to the increasing number of antibiotic-resistant strains, new strategies for eradication of H. pylori are needed. In this study, we suggest purine nucleoside phosphorylase (PNP) as a possible...

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Published in:Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.1083-1097
Main Authors: Narczyk, Marta, Wojtyś, Marta Ilona, Leščić Ašler, Ivana, Žinić, Biserka, Luić, Marija, Jagusztyn-Krynicka, Elżbieta Katarzyna, Štefanić, Zoran, Bzowska, Agnieszka
Format: Article
Language:English
Subjects:
Antibiotic resistance
Antibiotics
Binding Sites
Biophysics
Cell culture
Cell Culture Techniques
Drug development
Drugs
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzymes
Helicobacter pylori
Microorganisms
minimal inhibitory concentration
Nucleosides
Pathogens
Phosphorylase
Physical chemistry
Physics
Public health
purine nucleoside phosphorylase
Purine-Nucleoside Phosphorylase - chemistry
Purine-Nucleoside Phosphorylase - metabolism
Purines
Purines - chemistry
Purines - pharmacology
Research Paper
substituted purines
Therapeutic targets
Ulcers
X-ray structure
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Summary:Helicobacter pylori represents a global health threat with around 50% of the world population infected. Due to the increasing number of antibiotic-resistant strains, new strategies for eradication of H. pylori are needed. In this study, we suggest purine nucleoside phosphorylase (PNP) as a possible new drug target, by characterising its interactions with 2- and/or 6-substituted purines as well as the effect of these compounds on bacterial growth. Inhibition constants are in the micromolar range, the lowest being that of 6-benzylthio-2-chloropurine. This compound also inhibits H. pylori 26695 growth at the lowest concentration. X-ray structures of the complexes of PNP with the investigated compounds allowed the identification of interactions of inhibitors in the enzyme's base-binding site and the suggestion of structures that could bind to the enzyme more tightly. Our findings prove the potential of PNP inhibitors in the design of drugs against H. pylori.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2022.2061965