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  • Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus.

Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus.

PloS one (2022-12-09)
Sarah A Gilmore, Danny Tam, Tara L Cheung, Chelsea Snyder, Julie Farand, Ryan Dick, Mike Matles, Joy Y Feng, Ricardo Ramirez, Li Li, Helen Yu, Yili Xu, Dwight Barnes, Gregg Czerwieniec, Katherine M Brendza, Todd C Appleby, Gabriel Birkus, Madeleine Willkom, Tetsuya Kobayashi, Eric Paoli, Marc Labelle, Thomas Boesen, Chin H Tay, William E Delaney, Gregory T Notte, Uli Schmitz, Becket Feierbach
ABSTRACT

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 potential inhibitors of replication or gene expression. 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 reduced the levels of HBV RNA, DNA and antigen. 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-trimethyl-Histone H3 (Lys4) Antibody, Upstate®, from rabbit
Sigma-Aldrich
LSD1 Inhibitor II, S2101, The LSD1 Inhibitor II, S2101 controls the biological activity of LSD1. This small molecule/inhibitor is primarily used for Cell Signaling applications.
Sigma-Aldrich
3,3′,5,5′-Tetramethylbenzidine (TMB) Liquid Substrate System for ELISA, peroxidase substrate
Sigma-Aldrich
Camostat mesylate, ≥98% (HPLC)
Sigma-Aldrich
Trichostatin A, ≥98% (HPLC), from Streptomyces sp.