Synthesis and evaluation of ATP-binding site directed potential inhibitors of nucleoside triphosphatases/helicases and polymerases of hepatitis C and other selected Flaviviridae viruses.
5'-O-(4-fluorosulphonylbenzoyl)-esters of ribavirin (FSBR), adenosine (FSBA), guanosine (FSBG) and inosine (FSBI) were obtained by acylation of the 5'-OH of adenosine, guanosine, inosine, and ribavirin with 4-fluorosulphonylbenzoyl chloride (FSBCI) in HMPA. The above derivatives were tested as inhibitors of nucleoside triphosphatase (NTPase)/helicase activities of Flaviviridae: hepatitis C virus (HCV), West Nile virus (WNV), Japanese encephalitis virus (JEV) and dengue virus (DENV) and polymerase activity of HCV and WNV. When the unwinding activity of viral NTPase/helicases was tested under standard conditions, only weak inhibition was obtained with FSBI (IC50 > or = 120 microM) and in the case of FSBG even an activation was seen. The preincubation of the NTPase/helicases with the 5'-O-FSB derivatives increased the inhibitory effect. Screening of the 5'-O-FSB derivatives on inhibition of the WNV and HCV RNA polymerases employing GTP or UTP substrates revealed rather modest inhibitory effect. FSBI exhibited the highest inhibitory activity against WNV (IC50 = 70 microM with UTP substrate) and HCV polymerase (IC50 = 80 microM with GTP substrate). Other 5'-O-FSB derivatives were very weak inhibitors or completely failed to show any activity against HCV and WNV enzymes. In contrast to the NTPase/helicases the preincubation of the polymerases did not influence the inhibition.
Bretner
Maria
M
Laboratory of Antimetabolites, Institute of Biochemistry & Biophysics, Polish Academy of Sciences, Warszawa, Poland.
Schalinski
Sarah
S
Haag
Annemarie
A
Lang
Melanie
M
Schmitz
Herbert
H
Baier
Andrea
A
Behrens
Sven-E
SE
Kulikowski
Tadeusz
T
Borowski
Peter
P
D000255:Adenosine Triphosphate / Q000378:metabolism*; D001665:Binding Sites; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000737:chemistry; D018067:Flaviviridae / Q000201:enzymology*; D016174:Hepacivirus / Q000201:enzymology*; D015394:Molecular Structure; D043583:Nucleoside-Triphosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D004952:Esters; D011684:Purine Nucleosides; D000255:Adenosine Triphosphate; D012321:DNA-Directed RNA Polymerases; D043583:Nucleoside-Triphosphatase; D004265:DNA Helicases