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

Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify replication inhibitors. F...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Schmitz, Uli, Gilmore, Sarah A, Tam, Danny, Cheung, Tara L, Snyder, Chelsea, Farand, Julie, Ryan, Dick, Matles, Mike, Feng, Joy Y, Ramirez, Ricardo, Li, Li, Yu, Helen, Xu, Yili, Barnes, Dwight, Czerwieniec, Gregg, Brendza, Katherine M, Appleby, Todd C, Birkus, Gabriel, Willkom, Madeleine, Kobayashi, Tetsuya, Paoli, Eric, Labelle, Marc, Boesen, Thomas, Tay, Chin H, Delaney, William E, Notte, Gregory T, Becket Feierbach
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 30.06.2022
Subjects
Antiviral activity
Bioavailability
Chromatin
Chronic infection
Epigenetics
Health care
Hepatitis B
Hepatocytes
Histones
Interferon
Liver diseases
Lysine
Permeability
Pharmacodynamics
Public health
Replication
Viral diseases
Online AccessGet full text

Cover

More Information
Summary:Chronic hepatitis B (CHB) is a global health care challenge and a major cause of liver disease. To find new therapeutic avenues with a potential to functionally cure chronic Hepatitis B virus (HBV) infection, we performed a focused screen of epigenetic modifiers to identify replication inhibitors. From this work we identified isonicotinic acid inhibitors of the histone lysine demethylase 5 (KDM5) with potent anti-HBV activity. To enhance the cellular permeability and liver accumulation of the most potent KDM5 inhibitor identified (GS-080) an ester prodrug was developed (GS-5801) that resulted in improved bioavailability and liver exposure as well as an increased 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 from the in vitro model. Here we discuss potential reasons for the disconnect between in vitro and in vivo efficacy, which highlight the translational difficulties of epigenetic targets for viral diseases. Competing Interest Statement The authors have declared no competing interest. Footnotes * Author list has been corrected
DOI:10.1101/2022.06.27.497732