Synthesis, characterization, and inhibitory activities of nucleoside α,β-imido triphosphate analogues on human immunodeficiency virus-1 reverse transcriptase

Rongshi Li, Angelika Muscate, George L. Kenyon

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Six deoxynucleoside triphosphate (dNTP) analogues were synthesized, having the α,β-P-O-P bond replaced with an imido (P-N-P) functionality. They were all shown to be reasonably potent inhibitors of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT). This has permitted, for the first time, an estimate of the relative binding affinities of the parent triphosphates (dATP, TTP, dGTP, and dCTP) toward the enzyme's active site, in that they can be compared indirectly by correlation with the behavior of their α,β-imido analogues. Other complicating processes such as consecutive incorporation into the growing DNA chain can be excluded because the imido linkage cannot be cleaved by HIV-1 RT. The 5-iodo analog of deoxyuridine triphosphate (IdUMPNPP, 5) was the most potent inhibitor, having an IC50 value of 7 μM. A general route for the phosphorylation of purine and pyrimidine 5'-imidodiphosphates by pyruvate kinase was developed using phosphoenolpyruvate (PEP) as a phosphoryl group donor. Enzymatic phosphorylation was shown to be a more efficient approach than chemical methods.

Original languageEnglish (US)
Pages (from-to)251-261
Number of pages11
JournalBioorganic Chemistry
Volume24
Issue number3
DOIs
StatePublished - Sep 1996

Fingerprint

Phosphorylation
Nucleosides
Phosphoenolpyruvate
Pyruvate Kinase
Inhibitory Concentration 50
Catalytic Domain
DNA
Enzymes
Human immunodeficiency virus 1 reverse transcriptase
triphosphoric acid
imidodiphosphonic acid
deoxyguanosine triphosphate
2'-deoxycytidine 5'-triphosphate
thymidine 5'-triphosphate
pyrimidine
purine
deoxyuridine triphosphate

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

Cite this

Synthesis, characterization, and inhibitory activities of nucleoside α,β-imido triphosphate analogues on human immunodeficiency virus-1 reverse transcriptase. / Li, Rongshi; Muscate, Angelika; Kenyon, George L.

In: Bioorganic Chemistry, Vol. 24, No. 3, 09.1996, p. 251-261.

Research output: Contribution to journalArticle

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