Počet záznamů: 1
Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus
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SYSNO ASEP 0571883 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus Tvůrce(i) Gilmore, S. A. (US)
Tam, D. (US)
Cheung, T. L. (US)
Snyder, C. (US)
Farand, J. (US)
Dick, R. (US)
Matles, M. (US)
Feng, J. Y. (US)
Ramirez, R. (US)
Li, L. (US)
Yu, H. (US)
Xu, Y. (US)
Barnes, D. (US)
Czerwieniec, G. (US)
Brendza, K. M. (US)
Appleby, T. C. (US)
Birkuš, Gabriel (UOCHB-X) ORCID
Willkom, M. (US)
Kobayashi, T. (US)
Paoli, E. (US)
Labelle, M. (DK)
Boesen, T. (DK)
Tay, C. H. (US)
Delaney, W. E. (US)
Notte, G. T. (US)
Schmitz, U. (US)
Feierbach, B. (US)Číslo článku e0271145 Zdroj.dok. PLoS ONE. - : Public Library of Science - ISSN 1932-6203
Roč. 17, č. 12 (2022)Poč.str. 32 s. Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova histone modifications ; expression ; liver Obor OECD Virology Způsob publikování Open access Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000925063300004 EID SCOPUS 85143563961 DOI 10.1371/journal.pone.0271145 Anotace 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. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Rok sběru 2023 Elektronická adresa https://doi.org/10.1371/journal.pone.0271145
Počet záznamů: 1