C1'-Branched acyclic nucleoside phosphonates mimicking adenosine monophosphate: Potent inhibitors of Trypanosoma brucei adenine phosphoribosyltransferase
Language English Country France Media print-electronic
Document type Journal Article
PubMed
34482272
DOI
10.1016/j.ejmech.2021.113798
PII: S0223-5234(21)00647-4
Knihovny.cz E-resources
- Keywords
- APRT, Enzyme inhibitors, Nucleotide analogues, Phosphonates, Purine salvage pathway, Trypanosomiasis,
- MeSH
- Adenine Phosphoribosyltransferase antagonists & inhibitors metabolism MeSH
- Adenosine Monophosphate chemical synthesis chemistry pharmacology MeSH
- Antiprotozoal Agents chemical synthesis chemistry pharmacology MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Molecular Structure MeSH
- Nucleosides chemical synthesis chemistry pharmacology MeSH
- Parasitic Sensitivity Tests MeSH
- Trypanosoma brucei brucei drug effects enzymology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Adenine Phosphoribosyltransferase MeSH
- Adenosine Monophosphate MeSH
- Antiprotozoal Agents MeSH
- Enzyme Inhibitors MeSH
- Nucleosides MeSH
Some pathogens, including parasites of the genus Trypanosoma causing Human and Animal African Trypanosomiases, cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Thus, their PSP enzymes are considered as promising drug targets, sparsely explored so far. Recently, a significant role of acyclic nucleoside phosphonates (ANPs) as inhibitors of key enzymes of PSP, namely of 6-oxopurine phosphoribosyltransferases (PRTs), has been discovered. Herein, we designed and synthesized two series of new ANPs branched at the C1' position as mimics of adenosine monophosphate. The novel ANPs efficaciously inhibited Trypanosoma brucei adenine PRT (TbrAPRT1) activity in vitro and it was shown that the configuration on the C1' chiral centre strongly influenced their activity: the (R)-enantiomers proved to be more potent compared to the (S)-enantiomers. Two ANPs, with Ki values of 0.39 μM and 0.57 μM, represent the most potent TbrAPRT1 inhibitors reported to date and they are an important tool to further study purine metabolism in various parasites.
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