Design, synthesis, and antiviral activity of adenosine 5'-phosphonate analogues as chain terminators against hepatitis C virus.
A series of adenosine 5'-phosphonate analogues were designed to mimic naturally occurring adenosine monophosphate. These compounds (1-5) were synthesized and evaluated in a cellular hepatitis C virus (HCV) replication assay. To improve cellular permeability and enhance the anti-HCV activity of these phosphonates, a bis(S-acyl-2-thioethyl) prodrug for compound 5 was prepared, and its cellular activity was determined. To elucidate the mechanism of action of these novel adenosine phosphonates, their diphosphate derivatives (1a-5a) were synthesized. Further nucleotide incorporation assays by HCV NS5B RNA-dependent RNA polymerase revealed that 2a and 3a can serve as chain terminators, whereas compounds 1a, 4a, and 5a are competitive inhibitors with ATP. Additional steady-state kinetic analysis determined the incorporation efficiency of 2a and 3a as well as the inhibition constants for 1a, 4a, and 5a. The structure-activity relationships among these compounds were analyzed, and the implication for nucleoside phosphonate drug design was discussed.
Koh
Yung-hyo
YH
Drug Discovery, R&D, Valeant Pharmaceuticals International, 3300 Hyland Avenue, Costa Mesa, California 92626, USA.
Shim
Jae Hoon
JH
Wu
Jim Zhen
JZ
Zhong
Weidong
W
Hong
Zhi
Z
Girardet
Jean-Luc
JL
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004279:DNA, Viral / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003839:Deoxyadenosines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004279:DNA, Viral; D003839:Deoxyadenosines; D063065:Organophosphonates; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase