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Ko, C. ; Bester, R. ; Zhou, X.* ; Xu, Z.* ; Blossey, C. ; Sacherl, J. ; Vondran, F.W.R.* ; Gao, L.* ; Protzer, U.

A new role for capsid assembly modulators to target mature hepatitis B virus capsids and prevent virus infection.

Antimicrob. Agents Chemother. 64:e01440-19 (2019)
Verlagsversion Postprint DOI PMC
Open Access Green
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-log(10)-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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Antiviral Agents ; Capsid ; Core Protein ; Core Protein Allosteric Modulators ; Covalently Closed Circular Dna ; Hepatitis B Virus; Replication
ISSN (print) / ISBN 0066-4804
e-ISSN 1098-6596
Zeitschrift Antimicrobial Agents and Chemotherapy
Quellenangaben Band: 64, Heft: 1, Seiten: , Artikelnummer: e01440-19 Supplement: ,
Verlag American Society for Microbiology (ASM)
Verlagsort 1752 N St Nw, Washington, Dc 20036-2904 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)