Literature summary for 2.7.7.48 extracted from

Ali, S.; Leveque, V.; Le Pogam, S.; Ma, H.; Philipp, F.; Inocencio, N.; Smith, M.; Alker, A.; Kang, H.; Najera, I.; Klumpp, K.; Symons, J.; Cammack, N.; Jiang, W.R.
Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479 (2008), Antimicrob. Agents Chemother., 52, 4356-4369.

Cloned(Commentary)

Cloned (Comment)	Organism
wild-type and mutant enzymes, DNA and amino acid sequence determination and analysis	Hepacivirus C

Protein Variants

Protein Variants	Comment	Organism
A396G	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
A421V	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
C575S	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
I239L	the mutation occurs under PSI-6130 selection in cell culture, it increases the enzyme activity compared to the wild-type enzyme	Hepacivirus C
I239V	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
K72M	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
K72M/S282T	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
K72M/S282T/L564M	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
K81R	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
K81R/S282T	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
K81S/S282T	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
L320F	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
additional information	mutant activity analysis by transient replicon assay, overview	Hepacivirus C
S282S/T/C575S/Y586C	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme. The mutation of the NS5B polymerase mediates a three to sixfold loss of sensitivity to PSI-6130 compared to the wild-type enzyme, lack of cross-resistance between PSI-6130 and R1479, overview	Hepacivirus C
S282T/A396G	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/A421V	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/C575S	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/I239L	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/I239L/A396G	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/I239L/A396G/V485L	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/I239S	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/I239V	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/I239V/A396G	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/K81R/S84S/P I239L/A300T/L320F/L/C, A421V, Y586C	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/L320F	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/L320S	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S282T/Y586C	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C
S96T/N142T	the mutation of the NS5B polymerase mediates resistance to R7128. Long-term culture selection with PSI-6130 in replicon cells harboring preexisting mutation S96T/N142T results in the emergence of the S282T substitution and the reversion of S96T to wild-type serine	Hepacivirus C
Y586C	the mutation occurs under PSI-6130 selection in cell culture, it reduces the enzyme activity compared to the wild-type enzyme	Hepacivirus C

Inhibitors

Inhibitors	Comment	Organism
2'-C-methylcytidine	-	Hepacivirus C
4'-azidocytidine	-	Hepacivirus C
beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine	i.e. PSI-6130, a selective inhibitor of hepatitis C virus replication that targets the NS5B polymerase	Hepacivirus C
additional information	inhibitor efficiency with wild-type and mutant enzymes, overview	Hepacivirus C
NNI-1	-	Hepacivirus C
R7128	is the prodrug of PSI-6130, inhibits the enzyme and viral replication	Hepacivirus C

Organism

Organism	UniProt	Comment	Textmining
Hepacivirus C	B6EAV7	GT-1a and GT-1b clinical isolates	-

Specific Activity [micromol/min/mg]

Specific Activity Minimum [µmol/min/mg]	Specific Activity Maximum [µmol/min/mg]	Comment	Organism
additional information	-	relative activity of mutant enzymes compared to the wild-type enzyme, overview	Hepacivirus C

Synonyms

Synonyms	Comment	Organism
NS5B polymerase	-	Hepacivirus C

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism
0.000016	-	2'-C-methylcytidine	clinical isolate GT-1a	Hepacivirus C
0.000017	-	2'-C-methylcytidine	clinical isolate GT-1b	Hepacivirus C
0.000034	-	beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine	clinical isolate GT-1a	Hepacivirus C
0.00004	-	beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine	clinical isolate GT-1b	Hepacivirus C
0.000044	-	beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine	mutant S282T	Hepacivirus C
0.00058	-	2'-C-methylcytidine	mutant S282T	Hepacivirus C

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.00009	-	clinical isolate GT-1a	Hepacivirus C	2'-C-methylcytidine
0.00011	-	clinical isolate GT-1b	Hepacivirus C	beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine
0.00013	-	clinical isolate GT-1a	Hepacivirus C	beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine
0.00018	-	clinical isolate GT-1b	Hepacivirus C	2'-C-methylcytidine
0.0007	-	mutant S282T	Hepacivirus C	beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine
0.01	-	mutant S282T	Hepacivirus C	2'-C-methylcytidine