HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007)
Approximately 257 million people chronically infected with hepatitis B virus (HBV) worldwide are at risk of developing hepatocellular carcinoma (HCC). However, despite the availability of potent nucleoside/tide inhibitors, currently there are no curative therapies for chronic HBV infections. To iden...
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| Format: | Article |
| Language: | English |
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Wiley
2020-01-01
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| Series: | Advances in Virology |
| Online Access: | http://dx.doi.org/10.1155/2020/8844061 |
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| author | Raj Kalkeri Junzhong Peng Chunsheng Huang Zhaohui Cai Roger G. Ptak Mark J. Suto |
| author_facet | Raj Kalkeri Junzhong Peng Chunsheng Huang Zhaohui Cai Roger G. Ptak Mark J. Suto |
| author_sort | Raj Kalkeri |
| collection | DOAJ |
| description | Approximately 257 million people chronically infected with hepatitis B virus (HBV) worldwide are at risk of developing hepatocellular carcinoma (HCC). However, despite the availability of potent nucleoside/tide inhibitors, currently there are no curative therapies for chronic HBV infections. To identify potential new antiviral molecules, a select group of compounds previously evaluated in clinical studies were tested against 12 different viruses. Amongst the compounds tested, SRI-32007 (CYT997) demonstrated antiviral activity against HBV (genotype D) in HepG2.2.2.15 cell-based virus yield assay with 50% effective concentration (EC50) and selectivity index (SI) of 60.1 nM and 7.2, respectively. Anti-HBV activity of SRI-32007 was further confirmed against HBV genotype B in huh7 cells with secreted HBe antigen endpoint (EC50 40 nM and SI 250). To determine the stage of HBV life cycle inhibited by SRI-32007, time of addition experiment was conducted in HepG2-NTCP cell-based HBV infectious assay. Results indicated that SRI-32007 retained anti-HBV activity even when added 72 hours postinfection (72 h). Additional mechanism of action studies demonstrated potent inhibition of HBV core promoter activity by SRI-32007 with an EC50 of 40 nM and SI of >250. This study demonstrates anti-HBV activity of a repurposed compound SRI-32007 through inhibition of HBV core promoter activity. Further evaluation of SRI-32007 in HBV animal models is needed to confirm its activity in vivo. Our experiments illustrate the utility of repurposing strategy to identify novel antiviral chemical leads. HBV core promoter inhibitors such as SRI-32007 might enable the development of novel therapeutic strategies to combat HBV infections. |
| format | Article |
| id | doaj-art-c98647cde287425a892e25fb46e2df04 |
| institution | Kabale University |
| issn | 1687-8639 1687-8647 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advances in Virology |
| spelling | doaj-art-c98647cde287425a892e25fb46e2df042025-02-03T01:28:07ZengWileyAdvances in Virology1687-86391687-86472020-01-01202010.1155/2020/88440618844061HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007)Raj Kalkeri0Junzhong Peng1Chunsheng Huang2Zhaohui Cai3Roger G. Ptak4Mark J. Suto5Infectious Disease Research, Drug Development Division, Southern Research, Frederick, MD, USAInfectious Disease Research, Drug Development Division, Southern Research, Frederick, MD, USAInfectious Disease Research, Drug Development Division, Southern Research, Frederick, MD, USAInfectious Disease Research, Drug Development Division, Southern Research, Frederick, MD, USAInfectious Disease Research, Drug Development Division, Southern Research, Frederick, MD, USADrug Discovery, Southern Research, Birmingham, AL, USAApproximately 257 million people chronically infected with hepatitis B virus (HBV) worldwide are at risk of developing hepatocellular carcinoma (HCC). However, despite the availability of potent nucleoside/tide inhibitors, currently there are no curative therapies for chronic HBV infections. To identify potential new antiviral molecules, a select group of compounds previously evaluated in clinical studies were tested against 12 different viruses. Amongst the compounds tested, SRI-32007 (CYT997) demonstrated antiviral activity against HBV (genotype D) in HepG2.2.2.15 cell-based virus yield assay with 50% effective concentration (EC50) and selectivity index (SI) of 60.1 nM and 7.2, respectively. Anti-HBV activity of SRI-32007 was further confirmed against HBV genotype B in huh7 cells with secreted HBe antigen endpoint (EC50 40 nM and SI 250). To determine the stage of HBV life cycle inhibited by SRI-32007, time of addition experiment was conducted in HepG2-NTCP cell-based HBV infectious assay. Results indicated that SRI-32007 retained anti-HBV activity even when added 72 hours postinfection (72 h). Additional mechanism of action studies demonstrated potent inhibition of HBV core promoter activity by SRI-32007 with an EC50 of 40 nM and SI of >250. This study demonstrates anti-HBV activity of a repurposed compound SRI-32007 through inhibition of HBV core promoter activity. Further evaluation of SRI-32007 in HBV animal models is needed to confirm its activity in vivo. Our experiments illustrate the utility of repurposing strategy to identify novel antiviral chemical leads. HBV core promoter inhibitors such as SRI-32007 might enable the development of novel therapeutic strategies to combat HBV infections.http://dx.doi.org/10.1155/2020/8844061 |
| spellingShingle | Raj Kalkeri Junzhong Peng Chunsheng Huang Zhaohui Cai Roger G. Ptak Mark J. Suto HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007) Advances in Virology |
| title | HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007) |
| title_full | HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007) |
| title_fullStr | HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007) |
| title_full_unstemmed | HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007) |
| title_short | HBV Core Promoter Inhibition by Tubulin Polymerization Inhibitor (SRI-32007) |
| title_sort | hbv core promoter inhibition by tubulin polymerization inhibitor sri 32007 |
| url | http://dx.doi.org/10.1155/2020/8844061 |
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