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Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator

While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which mod...

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Autores principales: Hurwitz, Selwyn J., McBrearty, Noreen, Arzumanyan, Alla, Bichenkov, Eugene, Tao, Sijia, Bassit, Leda, Chen, Zhe, Kohler, James J., Amblard, Franck, Feitelson, Mark A., Schinazi, Raymond F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830897/
https://www.ncbi.nlm.nih.gov/pubmed/33467678
http://dx.doi.org/10.3390/v13010114
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author Hurwitz, Selwyn J.
McBrearty, Noreen
Arzumanyan, Alla
Bichenkov, Eugene
Tao, Sijia
Bassit, Leda
Chen, Zhe
Kohler, James J.
Amblard, Franck
Feitelson, Mark A.
Schinazi, Raymond F.
author_facet Hurwitz, Selwyn J.
McBrearty, Noreen
Arzumanyan, Alla
Bichenkov, Eugene
Tao, Sijia
Bassit, Leda
Chen, Zhe
Kohler, James J.
Amblard, Franck
Feitelson, Mark A.
Schinazi, Raymond F.
author_sort Hurwitz, Selwyn J.
collection PubMed
description While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3–3 log(10) versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log(10) titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold > in vitro EC(90) corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng·hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection.
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spelling pubmed-78308972021-01-26 Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator Hurwitz, Selwyn J. McBrearty, Noreen Arzumanyan, Alla Bichenkov, Eugene Tao, Sijia Bassit, Leda Chen, Zhe Kohler, James J. Amblard, Franck Feitelson, Mark A. Schinazi, Raymond F. Viruses Article While treatment options are available for hepatitis B virus (HBV), there is currently no cure. Anti-HBV nucleoside analogs and interferon-alpha 2b rarely clear HBV covalently closed circular DNA (cccDNA), requiring lifelong treatment. Recently, we identified GLP-26, a glyoxamide derivative which modulates HBV capsid assembly. The impact of GLP-26 on viral replication and integrated DNA was assessed in an HBV nude mouse model bearing HBV transfected AD38 xenografts. At day 45 post-infection, GLP-26 reduced HBV titers by 2.3–3 log(10) versus infected placebo-treated mice. Combination therapy with GLP-26 and entecavir reduced HBV log(10) titers by 4.6-fold versus placebo. Next, we examined the pharmacokinetics (PK) in cynomolgus monkeys administered GLP-26 via IV (1 mg/kg) or PO (5 mg/kg). GLP-26 was found to have 34% oral bioavailability, with a mean input time of 3.17 h. The oral dose produced a mean peak plasma concentration of 380.7 ng/mL, observed 0.67 h after administration (~30-fold > in vitro EC(90) corrected for protein binding), with a mean terminal elimination half-life of 2.4 h and a mean area under the plasma concentration versus time curve of 1660 ng·hr/mL. GLP-26 was 86.7% bound in monkey plasma. Lastly, GLP-26 demonstrated a favorable toxicity profile confirmed in primary human cardiomyocytes. Thus, GLP-26 warrants further preclinical development as an add on to treatment for HBV infection. MDPI 2021-01-15 /pmc/articles/PMC7830897/ /pubmed/33467678 http://dx.doi.org/10.3390/v13010114 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hurwitz, Selwyn J.
McBrearty, Noreen
Arzumanyan, Alla
Bichenkov, Eugene
Tao, Sijia
Bassit, Leda
Chen, Zhe
Kohler, James J.
Amblard, Franck
Feitelson, Mark A.
Schinazi, Raymond F.
Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator
title Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator
title_full Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator
title_fullStr Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator
title_full_unstemmed Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator
title_short Studies on the Efficacy, Potential Cardiotoxicity and Monkey Pharmacokinetics of GLP-26 as a Potent Hepatitis B Virus Capsid Assembly Modulator
title_sort studies on the efficacy, potential cardiotoxicity and monkey pharmacokinetics of glp-26 as a potent hepatitis b virus capsid assembly modulator
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830897/
https://www.ncbi.nlm.nih.gov/pubmed/33467678
http://dx.doi.org/10.3390/v13010114
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