biostudies-literatureWu RNIAID NIH HHS7958-66https://www.ebi.ac.uk/biostudies/studies/S-EPMC2990348biostudies-literatureUnknown53(22)Bioisosteric deaza analogues of 6-methyl-9-?-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-?-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-?-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.Journal of medicinal chemistrySynthesis of a 6-methyl-7-deaza analogue of adenosine that potently inhibits replication of polio and dengue viruses.PMC2990348AI054776U01 AI054776U01 AI082068-01U01 AI054776-05R01 AI070791R01 AI045818AI070791AI082068U01 AI082068R01 AI070791-01Cameron CEPadmanabhan RPeterson BRWu RSmidansky EDOh HSTakhampunya RfalseSynthesis 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-?-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-?-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-?-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.2010-01-01T00:00:00Z2010 Nov2020-10-31T08:20:47Z2019-03-27T00:36:50ZS-EPMC29903482096440610.1021/jm100593s