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| Status |
Public on Feb 24, 2021 |
| Title |
Characterization of a KDM5 Small Molecule Inhibitor with Antiviral Activity against Hepatitis B Virus |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. Existing therapies do not result in a functional cure in most individuals, necessitating new antiviral strategies against Hepatitis B virus (HBV). To identify additional therapeutic avenues, we performed a focused screen of epigenetic modifiers to identify inhibitors of HBV replication. From this work we identified small molecule inhibitors of the histone lysine demethylase 5 (KDM5) with antiviral activity against HBV. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) a prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as increased accumulation of the H3K4me3:H3 ratio on chromatin. GS-5801 treatment of HBV-infected primary human hepatocytes inhibited HBV replication and antigen levels. Evaluation of GS 5801 antiviral activity in a humanized mouse model of HBV infection, however, did not result in antiviral efficacy, despite achieving pharmacodynamic levels of H3K4me3:H3 predicted to be efficacious. Together these data highlight discordance between the antiviral effects of GS 5801 observed in HBV-infected primary human hepatocytes.
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| Overall design |
HBV-infected primary human hepatocytes from three donors were treated with GS-5801 every three to four days for 13 days and total cellular mRNA was isolated and sequenced on days 1, 3, 10, and 13 after initiation of dosing
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| Contributor(s) |
Gilmore S, Ramirez R, Willkom M, Birkus G, Li L |
| Citation missing |
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| |
| Submission date |
Jan 28, 2021 |
| Last update date |
Feb 24, 2021 |
| Contact name |
Ricardo Ramirez |
| Organization name |
Gilead Sciences, Inc.
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| Street address |
333 Lakeside Drive
|
| City |
Foster City |
| State/province |
CA |
| ZIP/Postal code |
94404 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (50)
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| Relations |
| BioProject |
PRJNA695546 |
| SRA |
SRP303689 |
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