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AASLD2017[937]
Heteroaryldihydropyrimidine compound GLS4
regulates both assembly and disassembly of
HBV capsids to inhibit cccDNA formation
Jianghua Wang1,4, Dong Jiang2, Yingjun Zhang3, Baohua
Gu3, Jinag Li3, Qingyun Ren3, Yong Li3, Yunfu Chen3, Xue-
Yan Wang1,4, Haiying Zhang1,4, Lai Wei1,4; 1Peking University
People’s Hospital, Peking University Hepatology Institute, Beijing,
China; 2Beijing Ditan Hospital, Capital Medical University,
Institute of Infectious Diseases, Beijing, China; 3Sunshine
Lake Pharma Co., Ltd., State Key Laboratory of Anti-Infective
Drug Development, Dongguan, China; 4Beijing Key Laboratory
of Hepatitis C and Immunotherapy for Liver Diseases,
Beijing, China
Background: Heteroaryldihydropyrimidine (HAP)
compounds inhibit hepatitis B virus (HBV) by interrupting
the assembly of HBV core antigen (HBcAg) dimers into
capsids. Effects of HAPs on the stability and function of
preformed HBV capsids, however, are not wellunderstood
and are being studied in this paper. Methods:Effects
of GLS4 on both assembly and disassemblyof HBV
capsids were investigated by using HBV-stably-expressing
HepAD38 cells and cell-free biophysical assays. Inhibitory
effects of GLS4 and entecavir (ETV) on formation ofcovalently
circular closed DNA (cccDNA) were evaluated in
HBV-infected HepG2-NTCP cells. Results:In HepAD38 cells,
GLS4 induced perinuclear aggregation and accelerated
degradation of HBcAg, followed with a highly effective
blockage of capsid assembly. Notably, GLS4 treatment
also caused nucleocapsid to migrate slower on native
agarose gel and quick degradations of preformed capsids
in cells. Further analysis of nucleocapsids (NCs) showed
that GLS4 specifically caused disassembly and degradation
of mature NCs containing double-stranded DNA, while
immature ones containing pgRNA or single-stranded DNA
were not affected. Data from cell-free biophysical assays
indicated that GLS4 could directly induce the disruption
of preformed capsids assembled with Cp149 proteins.
HepG2-NTCP-based HBV infectious assay showed that
GLS4, instead of ETV, treatment prior to virus inoculation
strongly inhibited the de novo formation of cccDNA
and concomitantly reduced the productionof HBsAg and
HBeAg. Conclusion: Taken together, we demonstrated in
the present study that GLS4 could dually regulate both
the assembly and disassembly of HBV capsids, resulting in
profound inhibition of cccDNA formation that is superior
to nucleot(s)ide analogues. Development of this kind of
capsid inhibitors then may be an advantageous strategy to
achieve better control of HBV infection.
Disclosures:
Lai Wei - Advisory Committees or Review Panels: Trek, Abbvie, Allergan,
Ascletis, BMS, Galmed, Gilead; Grant/Research Support: Abbvie, BMS,
Roche; Speaking and Teaching: Abbott, Abbvie, Ascletis, BMS, JNJ, MSD,
Gilead
The following people have nothing to disclose: Jianghua Wang, Dong Jiang,
Yingjun Zhang, Baohua Gu, Jinag Li, Qingyun Ren, Yong Li, Yunfu Chen,
Xue-Yan Wang, Haiying Zhang
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发表于 2017-10-20 20:21
