A novel, small anti-HBV compound reduces HBsAg and HBV-DNA by destabilizing HBV-RNA
© 2024. Japanese Society of Gastroenterology..
BACKGROUND: Currently, standard treatments for chronic hepatitis B such as nucleos(t)ide analogs (NAs), effectively reduce hepatitis B virus (HBV) loads but rarely result in a functional cure (defined as sustained HBsAg loss). We report the discovery of a novel, 4-pyridone compound, SAG-524, a potent and orally bioavailable small molecule inhibitor of HBV replication.
METHODS: The antiviral characteristics and selectivity of SAG-524 and its derivative compound against HBV were evaluated in HBV-infection assays and HBV-infected chimeric urokinase-type plasminogen activator/severe combined immunodeficiency mice with humanized livers (PXB mice), alone or in combination with entecavir. Toxicity studies were conducted in mice and monkeys.
RESULTS: SAG-524 reduced HBV-DNA (IC50 = 0.92 nM) and HBsAg (IC50 = 1.4 nM) in the supernatant of the HepG2.2.15 cells. SAG-524 selectively destabilized HBV-RNA via PAPD5, but not GAPDH or albumin mRNA, by shortening the poly(A) tail. PAPD5 may also be involved in HBV regulation via ELAVL1. In a study of HBV-infected PXB mice, SAG-524 produced potent reductions of serum HBsAg and HBcrAg, and the minimum effective dose was estimated to be 6 mg/kg/day. The combination therapy with entecavir greatly reduced HBsAg and cccDNA in the liver due to reduction of human hepatocytes with good tolerability. Administration of SAG-524 to monkeys, up to 1000 mg/kg/day for two weeks, led to no significant toxicity, as determined by blood tests and pathological images.
CONCLUSIONS: We have identified SAG-524 as novel and orally bioavailable HBV-RNA destabilizers which can reduce HBsAg and HBV-DNA levels, and possibly contribute a functional cure.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:59 |
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| Enthalten in: |
Journal of gastroenterology - 59(2024), 4 vom: 25. März, Seite 315-328 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Watanabe, Takehisa [VerfasserIn] |
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| Links: |
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| Themen: |
4-pyridone compound |
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| Anmerkungen: |
Date Completed 25.03.2024 Date Revised 25.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00535-023-02070-y |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368047113 |
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| 100 | 1 | |a Watanabe, Takehisa |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A novel, small anti-HBV compound reduces HBsAg and HBV-DNA by destabilizing HBV-RNA |
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| 500 | |a Date Revised 25.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. Japanese Society of Gastroenterology. | ||
| 520 | |a BACKGROUND: Currently, standard treatments for chronic hepatitis B such as nucleos(t)ide analogs (NAs), effectively reduce hepatitis B virus (HBV) loads but rarely result in a functional cure (defined as sustained HBsAg loss). We report the discovery of a novel, 4-pyridone compound, SAG-524, a potent and orally bioavailable small molecule inhibitor of HBV replication | ||
| 520 | |a METHODS: The antiviral characteristics and selectivity of SAG-524 and its derivative compound against HBV were evaluated in HBV-infection assays and HBV-infected chimeric urokinase-type plasminogen activator/severe combined immunodeficiency mice with humanized livers (PXB mice), alone or in combination with entecavir. Toxicity studies were conducted in mice and monkeys | ||
| 520 | |a RESULTS: SAG-524 reduced HBV-DNA (IC50 = 0.92 nM) and HBsAg (IC50 = 1.4 nM) in the supernatant of the HepG2.2.15 cells. SAG-524 selectively destabilized HBV-RNA via PAPD5, but not GAPDH or albumin mRNA, by shortening the poly(A) tail. PAPD5 may also be involved in HBV regulation via ELAVL1. In a study of HBV-infected PXB mice, SAG-524 produced potent reductions of serum HBsAg and HBcrAg, and the minimum effective dose was estimated to be 6 mg/kg/day. The combination therapy with entecavir greatly reduced HBsAg and cccDNA in the liver due to reduction of human hepatocytes with good tolerability. Administration of SAG-524 to monkeys, up to 1000 mg/kg/day for two weeks, led to no significant toxicity, as determined by blood tests and pathological images | ||
| 520 | |a CONCLUSIONS: We have identified SAG-524 as novel and orally bioavailable HBV-RNA destabilizers which can reduce HBsAg and HBV-DNA levels, and possibly contribute a functional cure | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 4-pyridone compound | |
| 650 | 4 | |a HBV-RNA destabilization | |
| 650 | 4 | |a HBsAg reduction | |
| 650 | 4 | |a PAPD5 | |
| 650 | 4 | |a SAG-524 | |
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| 700 | 1 | |a Hayashi, Sanae |e verfasserin |4 aut | |
| 700 | 1 | |a Zhaoyu, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Inada, Hiroki |e verfasserin |4 aut | |
| 700 | 1 | |a Nagaoka, Katsuya |e verfasserin |4 aut | |
| 700 | 1 | |a Tateyama, Masakuni |e verfasserin |4 aut | |
| 700 | 1 | |a Tanaka, Yasuhito |e verfasserin |4 aut | |
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