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In cell culture models, AB-423 showed potent inhibition of HBV replication (50% effective concentration [EC\n                    <jats:sub>50<\/jats:sub>\n                    ] = 0.08 to 0.27 \u03bcM; EC\n                    <jats:sub>90<\/jats:sub>\n                    = 0.33 to 1.32 \u03bcM) with no significant cytotoxicity (50% cytotoxic concentration &gt; 10 \u03bcM). Addition of 40% human serum resulted in a 5-fold increase in the EC\n                    <jats:sub>50<\/jats:sub>\n                    s. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variants\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In a\n                    <jats:italic>de novo<\/jats:italic>\n                    infection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein.\n                    <jats:italic>In vitro<\/jats:italic>\n                    dual combination studies with AB-423 and anti-HBV agents, such as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher levels of accumulation in the liver. A 7-day twice-daily administration of AB-423 in a hydrodynamic injection mouse model of HBV infection resulted in a dose-dependent reduction in serum HBV DNA levels, and combination with entecavir or ARB-1467 resulted in a trend toward antiviral activity greater than that of either agent alone, consistent with the results of the\n                    <jats:italic>in vitro<\/jats:italic>\n                    combination studies. The overall preclinical profile of AB-423 supports its further evaluation for safety, pharmacokinetics, and antiviral activity in patients with chronic hepatitis B.\n                  <\/jats:p>","DOI":"10.1128\/aac.00082-18","type":"journal-article","created":{"date-parts":[[2018,3,16]],"date-time":"2018-03-16T09:47:01Z","timestamp":1521193621000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":55,"title":["Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation"],"prefix":"10.1128","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8446-2338","authenticated-orcid":false,"given":"Nagraj","family":"Mani","sequence":"first","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew G.","family":"Cole","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet R.","family":"Phelps","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Ardzinski","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle D.","family":"Cobarrubias","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cuconati","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Dorsey","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Evangelista","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristi","family":"Fan","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Guo","sequence":"additional","affiliation":[{"name":"Arbutus Biopharma Inc., Warminster, Pennsylvania, USA, and Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Guo","sequence":"additional","affiliation":[{"name":"Indiana University, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju-Tao","family":"Guo","sequence":"additional","affiliation":[{"name":"Baruch S. 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