Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F22%3A00571883" target="_blank" >RIV/61388963:_____/22:00571883 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1371/journal.pone.0271145" target="_blank" >https://doi.org/10.1371/journal.pone.0271145</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1371/journal.pone.0271145" target="_blank" >10.1371/journal.pone.0271145</a>
Alternative languages
Result language
angličtina
Original language name
Characterization of a KDM5 small molecule inhibitor with antiviral activity against hepatitis B virus
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10607 - Virology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
PLoS ONE
ISSN
1932-6203
e-ISSN
1932-6203
Volume of the periodical
17
Issue of the periodical within the volume
12
Country of publishing house
US - UNITED STATES
Number of pages
32
Pages from-to
e0271145
UT code for WoS article
000925063300004
EID of the result in the Scopus database
2-s2.0-85143563961