TY - JOUR
T1 - A new role for capsid assembly modulators to target mature hepatitis B virus capsids and prevent virus infection
AU - Ko, Chunkyu
AU - Bester, Romina
AU - Zhou, Xue
AU - Xu, Zhiheng
AU - Blossey, Christoph
AU - Sacherl, Julia
AU - Vondran, Florian W.R.
AU - Gao, Lu
AU - Protzer, Ulrike
N1 - Publisher Copyright:
© 2019 American Society for Microbiology. All Rights Reserved.
PY - 2020
Y1 - 2020
N2 - Hepatitis B virus (HBV) is a major human pathogen, killing an estimated 887,000 people per year. Therefore, potentially curative therapies are of high importance. Following infection, HBV deposits a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that serves as a transcription template and is not affected by current therapies. HBV core protein allosteric modulators (CpAMs) prevent correct capsid assembly but may also affect early stages of HBV infection. In this study, we aimed to determine the antiviral efficacy of a novel, structurally distinct heteroaryldihydropyrimidine (HAP)-type CpAM, HAP_R01, and investigated whether and how HAP_R01 prevents the establishment of HBV infection. HAP_R01 shows a significant inhibition of cccDNA formation when applied during the first 48 h of HBV infection. Inhibiting cccDNA formation, however, requires >1-log10-higher concentrations than inhibition of the assembly of newly forming capsids (half-maximal effective concentration [EC50], 345 to 918 nM versus 26.8 to 43.5 nM, respectively). Biophysical studies using a new method to detect the incoming capsid in de novo infection revealed that HAP_R01 can physically change mature capsids of incoming virus particles and affect particle integrity. Treating purified HBV virions with HAP_R01 reduced their infectivity, highlighting the unique antiviral activity of CpAMs to target the capsid within mature HBV particles. Accordingly, HAP_R01 shows an additive antiviral effect in limiting de novo infection when combined with viral entry inhibitors. In summary, HAP_R01 perturbs capsid integrity of incoming virus particles and reduces their infectivity and thus inhibits cccDNA formation in addition to preventing HBV capsid assembly.
AB - Hepatitis B virus (HBV) is a major human pathogen, killing an estimated 887,000 people per year. Therefore, potentially curative therapies are of high importance. Following infection, HBV deposits a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that serves as a transcription template and is not affected by current therapies. HBV core protein allosteric modulators (CpAMs) prevent correct capsid assembly but may also affect early stages of HBV infection. In this study, we aimed to determine the antiviral efficacy of a novel, structurally distinct heteroaryldihydropyrimidine (HAP)-type CpAM, HAP_R01, and investigated whether and how HAP_R01 prevents the establishment of HBV infection. HAP_R01 shows a significant inhibition of cccDNA formation when applied during the first 48 h of HBV infection. Inhibiting cccDNA formation, however, requires >1-log10-higher concentrations than inhibition of the assembly of newly forming capsids (half-maximal effective concentration [EC50], 345 to 918 nM versus 26.8 to 43.5 nM, respectively). Biophysical studies using a new method to detect the incoming capsid in de novo infection revealed that HAP_R01 can physically change mature capsids of incoming virus particles and affect particle integrity. Treating purified HBV virions with HAP_R01 reduced their infectivity, highlighting the unique antiviral activity of CpAMs to target the capsid within mature HBV particles. Accordingly, HAP_R01 shows an additive antiviral effect in limiting de novo infection when combined with viral entry inhibitors. In summary, HAP_R01 perturbs capsid integrity of incoming virus particles and reduces their infectivity and thus inhibits cccDNA formation in addition to preventing HBV capsid assembly.
KW - Antiviral agents
KW - Capsid
KW - Core protein
KW - Core protein allosteric modulators
KW - Covalently closed circular DNA
KW - Hepatitis B virus
UR - http://www.scopus.com/inward/record.url?scp=85077016671&partnerID=8YFLogxK
U2 - 10.1128/AAC.01440-19
DO - 10.1128/AAC.01440-19
M3 - Article
C2 - 31658963
AN - SCOPUS:85077016671
SN - 0066-4804
VL - 64
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 1
M1 - e01440-19
ER -