[Non-hydrolysable analogs of inorganic pyrophosphate as inhibitors of hepatitis C virus RNA-dependent RNA-polymerase].
Inorganic pyrophosphate (PPi) is a product of the polymerization reaction catalyzed by DNA- and RNA-polymerases. We have synthesized a number of novel non-hydrolysable PPi analogues, some of them have demonstrated inhibition of polymerization reaction catalyzed by hepatitis C virus RNA-dependent RNA-polymerase (NS5B). A new pharmacophore has been developed based on non-hydrolysable methylene-diphosphonate backbone. Structure-activity relationship analysis of 12 bisphosphonates is presented and structural features crucial for the ability of molecule to inhibit NS5B polymerase activity are ascertained.
D V
DV
Ianvarev
A N
AN
Korovina
N N
NN
Usanov
S N
SN
Kochetkov
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011756:Diphosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy / Q000201:enzymology; D012367:RNA, Viral / Q000096:biosynthesis / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000998:Antiviral Agents; D011756:Diphosphates; D004791:Enzyme Inhibitors; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase