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Characterization of a KDM5 Small Molecule Inhibitor with Antiviral Activity against Hepatitis B Virus

ABSTRACT: Characterization of a KDM5 Small Molecule Inhibitor with Antiviral Activity against Hepatitis B Virus

PROVIDER: PRJNA695546 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13573000_1.fastq.gz	Fastqsanger.gz
	SRR13573000_2.fastq.gz	Fastqsanger.gz
	SRR13573001_1.fastq.gz	Fastqsanger.gz
	SRR13573001_2.fastq.gz	Fastqsanger.gz
	SRR13573002_1.fastq.gz	Fastqsanger.gz

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Characterization of a KDM5 Small Molecule Inhibitor with Antiviral Activity against Hepatitis B Virus

Project description: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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