{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:15:22Z","timestamp":1790309722781,"version":"4.1.0"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2019,3,7]],"date-time":"2019-03-07T00:00:00Z","timestamp":1551916800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,7]]},"abstract":"<jats:p>\n                    Hepatitis B e antigen (HBeAg) is an important immunomodulator for promoting host immune tolerance during chronic hepatitis B (CHB) infection. In patients with CHB, HBeAg loss and seroconversion represent partial immune control of CHB infection and are regarded as valuable endpoints. However, the current approved treatments have only a limited efficacy in achieving HBeAg seroconversion in HBeAg\u2010positive patients. Hepatitis B virus (HBV) core protein has been recognized as an attractive antiviral target, and two classes of core protein allosteric modulator (CpAM) have been discovered: the phenylpropenamides (PPAs) and the heteroaryldihydropyrimidines (HAPs). However, their differentiation and potential therapeutic benefit beyond HBV DNA inhibition remain to be seen. Here, we show that in contrast to PPA series compound AT\u2010130, a HAP CpAM, HAP_R01, reduced HBeAg levels in multiple\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                    HBV experimental models. Mechanistically, we found that HAP_R01 treatment caused the misassembly of capsids formed by purified HBeAg\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    . In addition, HAP_R01 directly reduces HBeAg levels by inducing intracellular precore protein misassembly and aggregation. Using a HAP_R01\u2010resistant mutant, we found that HAP_R01\u2010mediated HBeAg and core protein reductions were mediated through the same mechanism. Furthermore, HAP_R01 treatment substantially reduced serum HBeAg levels in an HBV mouse model.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    Unlike PPA series compound AT\u2010130, HAP_R01 not only inhibits HBV DNA levels but also directly reduces HBeAg through induction of its misassembly. HAP_R01, as well as other similar CpAMs, has the potential to achieve higher anti\u2010HBeAg seroconversion rates than currently approved therapies for patients with CHB. Our findings also provide guidance for dose selection when designing clinical trials with molecules from HAP series.\n                  <\/jats:p>","DOI":"10.1002\/hep.30514","type":"journal-article","created":{"date-parts":[[2019,1,21]],"date-time":"2019-01-21T11:23:55Z","timestamp":1548069835000},"page":"11-24","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":31,"title":["Direct Inhibition of Hepatitis B e Antigen by Core Protein Allosteric Modulator"],"prefix":"10.1097","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8463-1891","authenticated-orcid":false,"given":"Zhipeng","family":"Yan","sequence":"first","affiliation":[{"name":"Roche Innovation Center Shanghai,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daitze","family":"Wu","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Shanghai,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Hu","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Shanghai,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zeng","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Shanghai,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yu","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Shanghai,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiheng","family":"Xu","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Shanghai,Shanghai,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Roche Innovation Center 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