Inhibition of hepatitis B virus DNA polymerase by 3′-fluorothymidine triphosphate and other modified nucleoside triphosphate analogs

✍ Scribed by H. Meisel; K. Reimer; M. V. Janta-Lipinski; D. Bärwolff; E. Matthes

• Publisher: John Wiley and Sons
• Year: 1990
• Tongue: English
• Weight: 422 KB
• Volume: 30
• Category: Article
• ISSN: 0146-6615
• DOI: 10.1002/jmv.1890300211

✦ Synopsis

Abstract

The 3′‐fluoromodified nucleotide analogs 3′‐fluorothymidine triphosphate (FdTTP), 2′,3′‐dideoxy‐3′‐fluoro‐5‐chlorouridine triphosphate (F‐5CldUTP), 2′,3′‐dideoxy‐3′‐fluoro‐5‐ethyluridine triphosphate (F‐5EtdUTP), 2′,3′‐dideoxy‐3′‐fluorouridine triphosphate (FdUTP), and 2′,3′‐dideoxy‐3′‐fluoro‐5‐fluorouridine triphosphate (F‐5FdUTP) as well as 2′,3′‐dideoxythymidine triphosphate (ddTTP), 2′,3′‐didehydro‐2′,3′‐dideoxythymidine triphosphate (ddeTTP), 3′‐chlorothymidine triphosphate (CldTTP), and 3′‐rhodanothymidine triphosphate (SCNdTTP) were tested for their ability to inhibit hepatitis B virus (HBV)‐associated DNA polymerase activity in vitro. The ID~50~ values of the most potent inhibitors were 0.15 μM for FdTTP, 0.2 μM for ddeTTP, 0.45 μM for ddTTP, and 0.8 μM for F‐5CldUTP. SCNdTTP, CldTTP, and F‐5EtdUTP were less efficient (ID~50~ = 3–5 μM), and FdUTP and F‐5FdUTP were the least efficient inhibitors (ID~50~ = 25 μM) of the enzyme activity. Kinetic analysis revealed a competitive type of inhibition for FdTTP and ddeTTP. The K~i~ values were estimated to be 0.04 μM and 0.08 μM, respectively, compared with a K~m~ value for dTTP of about 0.18 μM.