Helicobacter pylori Xanthine–Guanine–Hypoxanthine Phosphoribosyltransferase—A Putative Target for Drug Discovery against Gastrointestinal Tract Infections

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F21%3A00542267" target="_blank" >RIV/61388963:_____/21:00542267 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jmedchem.0c02184" target="_blank" >https://doi.org/10.1021/acs.jmedchem.0c02184</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.0c02184" target="_blank" >10.1021/acs.jmedchem.0c02184</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Helicobacter pylori Xanthine–Guanine–Hypoxanthine Phosphoribosyltransferase—A Putative Target for Drug Discovery against Gastrointestinal Tract Infections

Popis výsledku v původním jazyce

Helicobacter pylori (Hp) is a human pathogen that lives in the gastric mucosa of approximately 50% of the world’s population causing gastritis, peptic ulcers, and gastric cancer. An increase in resistance to current drugs has sparked the search for new Hp drug targets and therapeutics. One target is the disruption of nucleic acid production, which can be achieved by impeding the synthesis of 6-oxopurine nucleoside monophosphates, the precursors of DNA and RNA. These metabolites are synthesized by Hp xanthine–guanine–hypoxanthine phosphoribosyltransferase (XGHPRT). Here, nucleoside phosphonates have been evaluated, which inhibit the activity of this enzyme with Ki values as low as 200 nM. The prodrugs of these compounds arrest the growth of Hp at a concentration of 50 μM in cell-based assays. The kinetic properties of HpXGHPRT have been determined together with its X-ray crystal structure in the absence and presence of 9-[(N-3-phosphonopropyl)-aminomethyl-9-deazahypoxanthine, providing a basis for new antibiotic development.

Název v anglickém jazyce

Helicobacter pylori Xanthine–Guanine–Hypoxanthine Phosphoribosyltransferase—A Putative Target for Drug Discovery against Gastrointestinal Tract Infections

Popis výsledku anglicky

Helicobacter pylori (Hp) is a human pathogen that lives in the gastric mucosa of approximately 50% of the world’s population causing gastritis, peptic ulcers, and gastric cancer. An increase in resistance to current drugs has sparked the search for new Hp drug targets and therapeutics. One target is the disruption of nucleic acid production, which can be achieved by impeding the synthesis of 6-oxopurine nucleoside monophosphates, the precursors of DNA and RNA. These metabolites are synthesized by Hp xanthine–guanine–hypoxanthine phosphoribosyltransferase (XGHPRT). Here, nucleoside phosphonates have been evaluated, which inhibit the activity of this enzyme with Ki values as low as 200 nM. The prodrugs of these compounds arrest the growth of Hp at a concentration of 50 μM in cell-based assays. The kinetic properties of HpXGHPRT have been determined together with its X-ray crystal structure in the absence and presence of 9-[(N-3-phosphonopropyl)-aminomethyl-9-deazahypoxanthine, providing a basis for new antibiotic development.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/GA19-07707S" target="_blank" >GA19-07707S: Acyklické nukleosidfosfonáty jako potenciální inhibitory adenin fosforibosyltransferáz lidských trypanozomálních parazitů</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

64

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

20

Strana od-do

5710-5729

Kód UT WoS článku

000651785800029

EID výsledku v databázi Scopus

2-s2.0-85106100493