Synthesis and evaluation of ATP-binding site directed potential inhibitors of nucleoside triphosphatases/helicases and polymerases of hepatitis C and other selected Flaviviridae viruses.
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Synthesis and evaluation of ATP-binding site directed potential inhibitors of nucleoside triphosphatases/helicases and polymerases of hepatitis C and other selected Flaviviridae viruses. / Bretner, Maria; Schalinski, Sarah; Haag, Annemarie; Lang, Melanie; Schmitz, Herbert; Baier, Andrea; Behrens, Sven-E; Kulikowski, Tadeusz; Borowski, Peter.
in: ANTIVIR CHEM CHEMOTH, Jahrgang 15, Nr. 1, 1, 2004, S. 35-42.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Synthesis and evaluation of ATP-binding site directed potential inhibitors of nucleoside triphosphatases/helicases and polymerases of hepatitis C and other selected Flaviviridae viruses.
AU - Bretner, Maria
AU - Schalinski, Sarah
AU - Haag, Annemarie
AU - Lang, Melanie
AU - Schmitz, Herbert
AU - Baier, Andrea
AU - Behrens, Sven-E
AU - Kulikowski, Tadeusz
AU - Borowski, Peter
PY - 2004
Y1 - 2004
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 15
SP - 35
EP - 42
JO - ANTIVIR CHEM CHEMOTH
JF - ANTIVIR CHEM CHEMOTH
SN - 0956-3202
IS - 1
M1 - 1
ER -