Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731
ABI-H0731, a first-generation hepatitis B virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a phase 1b clinical trial and is currently being further evaluated in phase 2 clinical trials. Here, we report the preclinical profile...
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Veröffentlicht in: | Antimicrobial agents and chemotherapy 2020-10, Vol.64 (11) |
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container_title | Antimicrobial agents and chemotherapy |
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creator | Huang, Qi Cai, Dawei Yan, Ran Li, Lichun Zong, Yuhua Guo, Lida Mercier, Alexandre Zhou, Yi Tang, Ariel Henne, Kirk Colonno, Richard |
description | ABI-H0731, a first-generation hepatitis B virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a phase 1b clinical trial and is currently being further evaluated in phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2-derived cell lines HepAD38 and HepG2-NTCP and primary human hepatocytes [PHHs]), ABI-H0731 exhibited selective inhibition of HBV DNA replication (50% effective concentration [EC50] from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed covalently closed circular DNA (cccDNA) formation in two de novo infection models with EC50s from 1.84 μM to 7.3 μM. Mechanism-of-action studies indicated that ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. The combination of ABI-H0731 with entecavir appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogue (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing the premature release of relaxed circular DNA (rcDNA) before delivery to the nucleus, and thus prevents new cccDNA formation. ABI-H0731 exhibits pangenotypic activity and is additive to moderately synergistic when combined with an NrtI. In addition to its potency and novel mechanism of action, ABI-H0731 possesses drug-like properties and a preclinical pharmacokinetic profile supportive of once-daily dosing in patients with CHB. Taken together, these data support the ongoing clinical development of ABI-H0731 as a treatment for HBV. |
doi_str_mv | 10.1128/AAC.01463-20 |
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Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2-derived cell lines HepAD38 and HepG2-NTCP and primary human hepatocytes [PHHs]), ABI-H0731 exhibited selective inhibition of HBV DNA replication (50% effective concentration [EC50] from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed covalently closed circular DNA (cccDNA) formation in two de novo infection models with EC50s from 1.84 μM to 7.3 μM. Mechanism-of-action studies indicated that ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. The combination of ABI-H0731 with entecavir appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogue (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing the premature release of relaxed circular DNA (rcDNA) before delivery to the nucleus, and thus prevents new cccDNA formation. ABI-H0731 exhibits pangenotypic activity and is additive to moderately synergistic when combined with an NrtI. In addition to its potency and novel mechanism of action, ABI-H0731 possesses drug-like properties and a preclinical pharmacokinetic profile supportive of once-daily dosing in patients with CHB. Taken together, these data support the ongoing clinical development of ABI-H0731 as a treatment for HBV.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/AAC.01463-20</identifier><identifier>PMID: 32868329</identifier><language>eng</language><publisher>1752 N St., N.W., Washington, DC: American Society for Microbiology</publisher><subject>Antiviral Agents</subject><ispartof>Antimicrobial agents and chemotherapy, 2020-10, Vol.64 (11)</ispartof><rights>Copyright © 2020 Huang et al.</rights><rights>Copyright © 2020 Huang et al. 2020 Huang et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a461t-98ec571f6d4f0c4b6cb0240618add0efd39b64d6d55767268270da00dd3eb9f83</citedby><cites>FETCH-LOGICAL-a461t-98ec571f6d4f0c4b6cb0240618add0efd39b64d6d55767268270da00dd3eb9f83</cites><orcidid>0000-0001-5381-3716</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577125/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577125/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Huang, Qi</creatorcontrib><creatorcontrib>Cai, Dawei</creatorcontrib><creatorcontrib>Yan, Ran</creatorcontrib><creatorcontrib>Li, Lichun</creatorcontrib><creatorcontrib>Zong, Yuhua</creatorcontrib><creatorcontrib>Guo, Lida</creatorcontrib><creatorcontrib>Mercier, Alexandre</creatorcontrib><creatorcontrib>Zhou, Yi</creatorcontrib><creatorcontrib>Tang, Ariel</creatorcontrib><creatorcontrib>Henne, Kirk</creatorcontrib><creatorcontrib>Colonno, Richard</creatorcontrib><title>Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><description>ABI-H0731, a first-generation hepatitis B virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a phase 1b clinical trial and is currently being further evaluated in phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2-derived cell lines HepAD38 and HepG2-NTCP and primary human hepatocytes [PHHs]), ABI-H0731 exhibited selective inhibition of HBV DNA replication (50% effective concentration [EC50] from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed covalently closed circular DNA (cccDNA) formation in two de novo infection models with EC50s from 1.84 μM to 7.3 μM. Mechanism-of-action studies indicated that ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. The combination of ABI-H0731 with entecavir appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogue (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing the premature release of relaxed circular DNA (rcDNA) before delivery to the nucleus, and thus prevents new cccDNA formation. ABI-H0731 exhibits pangenotypic activity and is additive to moderately synergistic when combined with an NrtI. In addition to its potency and novel mechanism of action, ABI-H0731 possesses drug-like properties and a preclinical pharmacokinetic profile supportive of once-daily dosing in patients with CHB. Taken together, these data support the ongoing clinical development of ABI-H0731 as a treatment for HBV.</description><subject>Antiviral Agents</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNptkVFrFDEUhYModm198wfksYJTbzKZTOalsDuou1CwD9bXkEnudFNmk22SEfTXO3WLIPh0OdzvngvnEPKOwRVjXH1cr_srYELWFYcXZMWgU5VsOvmSrACkrIQCcUbe5PwAi246eE3Oaq6kqnm3IsNtQjv54K2Z6G2Ko5-QmuBovzfJ2ILJ_zLFx0DjSMse6RaPiy4-0w397tOcaR8TPp0W9IHuwt4PvsRE15tdtYW2Zhfk1WimjG-f5zm5-_zpW7-tbr5-2fXrm8oIyUrVKbRNy0bpxAhWDNIOwAVIpoxzgKOru0EKJ13TtLLlUvEWnAFwrsahG1V9Tq5Pvsd5OKCzGEoykz4mfzDpp47G6383we_1ffyh26ZtGW8Wg8tngxQfZ8xFH3y2OE0mYJyz5qLuJF_yZAv64YTaFHNOOP59w0A_1aKXWvSfWjSHBX9_wk0-cP0Q5xSWJP7P_gZMQYrE</recordid><startdate>20201020</startdate><enddate>20201020</enddate><creator>Huang, Qi</creator><creator>Cai, Dawei</creator><creator>Yan, Ran</creator><creator>Li, Lichun</creator><creator>Zong, Yuhua</creator><creator>Guo, Lida</creator><creator>Mercier, Alexandre</creator><creator>Zhou, Yi</creator><creator>Tang, Ariel</creator><creator>Henne, Kirk</creator><creator>Colonno, Richard</creator><general>American Society for Microbiology</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5381-3716</orcidid></search><sort><creationdate>20201020</creationdate><title>Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731</title><author>Huang, Qi ; Cai, Dawei ; Yan, Ran ; Li, Lichun ; Zong, Yuhua ; Guo, Lida ; Mercier, Alexandre ; Zhou, Yi ; Tang, Ariel ; Henne, Kirk ; Colonno, Richard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a461t-98ec571f6d4f0c4b6cb0240618add0efd39b64d6d55767268270da00dd3eb9f83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Antiviral Agents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Qi</creatorcontrib><creatorcontrib>Cai, Dawei</creatorcontrib><creatorcontrib>Yan, Ran</creatorcontrib><creatorcontrib>Li, Lichun</creatorcontrib><creatorcontrib>Zong, Yuhua</creatorcontrib><creatorcontrib>Guo, Lida</creatorcontrib><creatorcontrib>Mercier, Alexandre</creatorcontrib><creatorcontrib>Zhou, Yi</creatorcontrib><creatorcontrib>Tang, Ariel</creatorcontrib><creatorcontrib>Henne, Kirk</creatorcontrib><creatorcontrib>Colonno, Richard</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Qi</au><au>Cai, Dawei</au><au>Yan, Ran</au><au>Li, Lichun</au><au>Zong, Yuhua</au><au>Guo, Lida</au><au>Mercier, Alexandre</au><au>Zhou, Yi</au><au>Tang, Ariel</au><au>Henne, Kirk</au><au>Colonno, Richard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><date>2020-10-20</date><risdate>2020</risdate><volume>64</volume><issue>11</issue><issn>0066-4804</issn><eissn>1098-6596</eissn><abstract>ABI-H0731, a first-generation hepatitis B virus (HBV) core protein inhibitor, has demonstrated effective antiviral activity in chronic hepatitis B (CHB) patients in a phase 1b clinical trial and is currently being further evaluated in phase 2 clinical trials. Here, we report the preclinical profile of ABI-H0731. In in vitro cell culture systems (HepG2-derived cell lines HepAD38 and HepG2-NTCP and primary human hepatocytes [PHHs]), ABI-H0731 exhibited selective inhibition of HBV DNA replication (50% effective concentration [EC50] from 173 nM to 307 nM). Most importantly, ABI-H0731 suppressed covalently closed circular DNA (cccDNA) formation in two de novo infection models with EC50s from 1.84 μM to 7.3 μM. Mechanism-of-action studies indicated that ABI-H0731 is a direct-acting antiviral that targets HBV core protein, preventing HBV pregenomic RNA (pgRNA) encapsidation and subsequent DNA replication. The combination of ABI-H0731 with entecavir appears to decrease viral DNA faster and deeper than nucleoside/nucleotide analogue (NrtI) therapy alone. In addition, ABI-H0731 disrupts incoming nucleocapsids, causing the premature release of relaxed circular DNA (rcDNA) before delivery to the nucleus, and thus prevents new cccDNA formation. ABI-H0731 exhibits pangenotypic activity and is additive to moderately synergistic when combined with an NrtI. In addition to its potency and novel mechanism of action, ABI-H0731 possesses drug-like properties and a preclinical pharmacokinetic profile supportive of once-daily dosing in patients with CHB. Taken together, these data support the ongoing clinical development of ABI-H0731 as a treatment for HBV.</abstract><cop>1752 N St., N.W., Washington, DC</cop><pub>American Society for Microbiology</pub><pmid>32868329</pmid><doi>10.1128/AAC.01463-20</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0001-5381-3716</orcidid><oa>free_for_read</oa></addata></record> |
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title | Preclinical Profile and Characterization of the Hepatitis B Virus Core Protein Inhibitor ABI-H0731 |
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