Synthesis and Evaluation of ATP-Binding Site Directed Potential Inhibitors of Nucleoside Triphosphatases/ Helicases and Polymerases of Hepatitis C and other Selected Flaviviridae Viruses

• Published in: Antiviral chemistry & chemotherapy Vol. 15; no. 1; pp. 35 - 42
• Main Authors: Bretner, Maria, Schalinski, Sarah, Haag, Annemarie, Lang, Melanie, Schmitz, Herbert, Baier, Andrea, Behrens, Sven-E, Kulikowski, Tadeusz, Borowski, Peter
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 2004; International Medical Press; Sage Publications Ltd
• Subjects: Acylation; Adenosine; Adenosine Triphosphate - metabolism; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Dengue fever; Dengue virus; DNA helicase; DNA Helicases - antagonists & inhibitors; DNA Helicases - metabolism; DNA-Directed RNA Polymerases - antagonists & inhibitors; DNA-Directed RNA Polymerases - metabolism; Encephalitis; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Esters; Esters - chemistry; Flaviviridae; Flaviviridae - enzymology; Flavivirus; Guanosine; Guanosine triphosphate; Hepacivirus - enzymology; Hepatitis; Hepatitis C; Hepatitis C virus; Japanese encephalitis virus; Medical sciences; Molecular Structure; Nucleoside-Triphosphatase - antagonists & inhibitors; Nucleoside-Triphosphatase - metabolism; Nucleosides; Pharmacology. Drug treatments; Purine Nucleosides - chemical synthesis; Purine Nucleosides - chemistry; Purine Nucleosides - pharmacology; Ribavirin; Ribonucleic acid; RNA; Triphosphatase; Unwinding; Viruses; West Nile virus; inhibitors; NTPase/helicase; HCV; RNA polymerase; Flaviviridae; Enzyme; Transferases; Enzyme inhibitor; Hepatic disease; Binding site; DNA-directed RNA polymerase; Infection; Virus; Nucleotidyltransferases; Nucleoside-triphosphatase; Viral disease; Digestive diseases; Hydrolases; Antiviral; Chemical synthesis; Hepatitis C virus; Hepacivirus; ATP
• ISSN: 2040-2066; 0956-3202; 2040-2066
• DOI: 10.1177/095632020401500104

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 (FSBCl) 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≥120 μM) 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 μM with UTP substrate) and HCV polymerase (IC50=80 μM 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.