Synthesis of a 6-methyl-7-deaza analogue of adenosine that potently inhibits replication of polio and dengue viruses.
Bioisosteric deaza analogues of 6-methyl-9-β-D-ribofuranosylpurine, a hydrophobic analogue of adenosine, were synthesized and evaluated for antiviral activity. Whereas the 1-deaza and 3-deaza analogues were essentially inactive in plaque assays of infectivity, a novel 7-deaza-6-methyl-9-β-D-ribofuranosylpurine analogue, structurally related to the natural product tubercidin, potently inhibited replication of poliovirus (PV) in HeLa cells (IC(50) = 11 nM) and dengue virus (DENV) in Vero cells (IC(50) = 62 nM). Selectivity against PV over cytotoxic effects to HeLa cells was >100-fold after incubation for 7 h. Mechanistic studies of the 5'-triphosphate of 7-deaza-6-methyl-9-β-D-ribofuranosylpurine revealed that this compound is an efficient substrate of PV RNA-dependent RNA polymerase (RdRP) and is incorporated into RNA mimicking both ATP and GTP.
Wu
Runzhi
R
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
Smidansky
Eric D
ED
Oh
Hyung Suk
HS
Takhampunya
Ratree
R
Padmanabhan
Radhakrishnan
R
Cameron
Craig E
CE
Peterson
Blake R
BR
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D003716:Dengue Virus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D017955:Poliovirus / Q000187:drug effects* / Q000502:physiology; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014773:Virology / Q000379:methods; D014779:Virus Replication
C554506:7-deaza-6-methyl-9-ribofuranosylpurine; D000998:Antiviral Agents; D011684:Purine Nucleosides; D000241:Adenosine