Direct inhibition of hepatitis B virus e antigen by core protein allosteric modulator

Abstract

Hepatitis B e antigen (HBeAg) is an important immunomodulator for promoting host immune tolerance during chronic hepatitis B (CHB) infection. In CHB patients, 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‐positive patients. 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‐130, a novel HAP CpAM, HAP_R01, reduced HBeAg levels in multiple in vitro and in vivo HBV experimental models. Mechanistically, we found that HAP_R01 treatment caused the misassembly of capsids formed by purified HBeAg in vitro. In addition, HAP_R01 directly reduces HBeAg levels by inducing intracellular precore protein misassembly and aggregation. Using a HAP_R01 resistant mutant, we found that this HAP_R01‐mediated HBeAg and core reductions were mediated via the same mechanism. Furthermore, HAP_R01 treatment substantially reduced serum HBeAg levels in an HBV mouse model. Conclusion Unlike PPA series compound AT‐130, HAP_R01 not only inhibits HBV DNA levels, but also directly reduces HBeAg via induction of its misassembly. HAP_R01, as well as other similar CpAMs, have the potential to achieve higher anti‐HBeAg seroconversion rates than currently approved therapies for CHB patients. Our findings also provide guidance for dose selection when designing clinical trials with molecules from HAP series.

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