Dataset Information

Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus.

ABSTRACT: PSI-7977, a prodrug of 2'-F-2'-C-methyluridine monophosphate, is the purified diastereoisomer of PSI-7851 and is currently being investigated in phase 3 clinical trials for the treatment of hepatitis C. In this study, we profiled the activity of PSI-7977 and its ability to select for resistance using a number of different replicon cells. Results showed that PSI-7977 was active against genotype (GT) 1a, 1b, and 2a (strain JFH-1) replicons and chimeric replicons containing GT 2a (strain J6), 2b, and 3a NS5B polymerase. Cross-resistance studies using GT 1b replicons confirmed that the S282T change conferred resistance to PSI-7977. Subsequently, we evaluated the ability of PSI-7977 to select for resistance using GT 1a, 1b, and 2a (JFH-1) replicon cells. S282T was the common mutation selected among all three genotypes, but while it conferred resistance to PSI-7977 in GT 1a and 1b, JFH-1 GT 2a S282T showed only a very modest shift in 50% effective concentration (EC(50)) for PSI-7977. Sequence analysis of the JFH-1 NS5B region indicated that additional amino acid changes were selected both prior to and after the emergence of S282T. These include T179A, M289L, I293L, M434T, and H479P. Residues 179, 289, and 293 are located within the finger and palm domains, while 434 and 479 are located on the surface of the thumb domain. Data from the JFH-1 replicon variants showed that amino acid changes within the finger and palm domains together with S282T were required to confer resistance to PSI-7977, while the mutations on the thumb domain serve to enhance the replication capacity of the S282T replicons.

SUBMITTER: Lam AM

PROVIDER: S-EPMC3370800 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus.

Lam Angela M AM Espiritu Christine C Bansal Shalini S Micolochick Steuer Holly M HM Niu Congrong C Zennou Veronique V Keilman Meg M Zhu Yuao Y Lan Shuiyun S Otto Michael J MJ Furman Phillip A PA

Antimicrobial agents and chemotherapy 20120319 6

PSI-7977, a prodrug of 2'-F-2'-C-methyluridine monophosphate, is the purified diastereoisomer of PSI-7851 and is currently being investigated in phase 3 clinical trials for the treatment of hepatitis C. In this study, we profiled the activity of PSI-7977 and its ability to select for resistance using a number of different replicon cells. Results showed that PSI-7977 was active against genotype (GT) 1a, 1b, and 2a (strain JFH-1) replicons and chimeric replicons containing GT 2a (strain J6), 2b, a ...[more]

PMID: 22430955

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Project description:BackgroundHepatitis C virus (HCV) is one of the leading causes of chronic liver disease. Seven genotypes and more than 80 subtypes have been identified for HCV so far. To date, 10 subtypes (3a to 3i; and 3k) of HCV genotype 3 have been identified. In 2006, two HCV isolates were reported from Iran that belonged to a new subtype of genotype 3. However, considering the consensus proposal for HCV genotype nomenclature, the available sequences of the new subtype did not correspond to the regions that are required to be analyzed prior to subtype assignment. During a study on the molecular epidemiology of HCV in Iran, an HCV isolate (FSM165) which seemed to belong to a new subtype of genotype 3 was obtained from a patient residing in Tehran, Iran.ObjectivesThe aim of this study was to assess the relatedness of isolate FM165 together with several sequences retrieved from the database to the new HCV-3 subtype reported from Iran in 2006.Materials and methodsVarious parts of the genome including the core/E1 region and two segments of the NS5B region were amplified and sequenced for isolate FSM165. Furthermore, using the Basic Local Alignment Search Tool (BLAST), the HCV database was searched for sequences that had a high level of similarity with sequences of FSM165 isolate and such sequences were retrieved from the database. To investigate the relatedness of isolate FSM165 and also the retrieved sequences to a new HCV-3 subtype reported previously, phylogenetic analyses were performed using the Kimura two-parameter model and the neighbor joining method.ResultsPhylogenetic analysis of the partial NS5B region demonstrated the relatedness of isolate FSM165 to the new subtype reported from Iran in 2006. Moreover, some core/E1 and NS5B sequences that had a high level of similarity with FSM165 isolate were found through searching the HCV database. These sequences were previously either misclassified or could not be accurately classified. Phylogenetic analyses showed that all of the described sequences belonged to the new subtype of HCV genotype 3.ConclusionsData suggests that the new subtype has a vast geographical distribution in Iran. The core/E1 and the NS5B sequences described in this paper can be used as references for the new HCV-3 subtype in future studies.

Dataset Information

Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus.

Publications

Genotype and subtype profiling of PSI-7977 as a nucleotide inhibitor of hepatitis C virus.

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