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Kao CC, Nie Y, Ren S, et al. Mechanism of action of hepatitis B virus S antigen transport-inhibiting oligonucleotide polymer, STOPS, molecules. Mol Ther Nucleic Acids. 2021;27:335-348doi: 10.1016/j.omtn.2021.12.013.
Kao, C. C., Nie, Y., Ren, S., De Costa, N. T. T. S., Pandey, R. K., Hong, J., Smith, D. B., Symons, J. A., Beigelman, L., & Blatt, L. M. (2022). Mechanism of action of hepatitis B virus S antigen transport-inhibiting oligonucleotide polymer, STOPS, molecules. Molecular therapy. Nucleic acids, 27335-348. https://doi.org/10.1016/j.omtn.2021.12.013
Kao, C Cheng, et al. "Mechanism of action of hepatitis B virus S antigen transport-inhibiting oligonucleotide polymer, STOPS, molecules." Molecular therapy. Nucleic acids vol. 27 (2022): 335-348. doi: https://doi.org/10.1016/j.omtn.2021.12.013
Kao CC, Nie Y, Ren S, De Costa NTTS, Pandey RK, Hong J, Smith DB, Symons JA, Beigelman L, Blatt LM. Mechanism of action of hepatitis B virus S antigen transport-inhibiting oligonucleotide polymer, STOPS, molecules. Mol Ther Nucleic Acids. 2021 Dec 11;27:335-348. doi: 10.1016/j.omtn.2021.12.013. eCollection 2022 Mar 08. PMID: 35024245; PMCID: PMC8717253.
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Mol Ther Nucleic Acids. 2021 Dec 11;27:335-348. doi: 10.1016/j.omtn.2021.12.013. eCollection 2022 Mar 08.

Mechanism of action of hepatitis B virus S antigen transport-inhibiting oligonucleotide polymer, STOPS, molecules.

Molecular therapy. Nucleic acids

C Cheng Kao, Yuchun Nie, Suping Ren, N Tilani T S De Costa, Rajendra K Pandey, Jin Hong, David B Smith, Julian A Symons, Leonid Beigelman, Lawrence M Blatt

Affiliations

  1. Aligos Therapeutics, Inc., 1 Corporate Drive, South San Francisco, CA 94080, USA.

PMID: 35024245 PMCID: PMC8717253 DOI: 10.1016/j.omtn.2021.12.013

Abstract

A functional cure of chronic hepatitis B requires eliminating the hepatitis B virus (HBV)-encoded surface antigen (HBsAg), which can suppress immune responses. STOPS are phosphorothioated single-stranded oligonucleotides containing novel chemistries that significantly reduce HBsAgs produced by HBV-infected liver cells. The STOPS molecule ALG-10000 functions inside cells to reduce the levels of multiple HBV-encoded molecules. However, it does not bind HBV molecules. An affinity resin coupled with ALG-10000 was found to bind several proteins from liver cells harboring replicating HBV. Silencing RNAs targeting host factors SRSF1, HNRNPA2B1, GRP78 (HspA5), RPLP1, and RPLP2 reduced HBsAg levels and other HBV molecules that are concomitantly reduced by STOPS. Host proteins RPLP1/RPLP2 and GRP78 function in the translation of membrane proteins, protein folding, and degradation. ALG-10000 and the knockdowns of RPLP1/2 and GRP78 decreased the levels of HBsAg and increased their ubiquitination and proteasome degradation. GRP78, RPLP1, and RPLP2 affected HBsAg production only when HBsAg was expressed with HBV regulatory sequences, suggesting that HBV has evolved to engage with these STOPS-interacting molecules. The STOPS inhibition of HBsAg levels in HBV-infected cells occurs by sequestering cellular proteins needed for proper expression and folding of HBsAg.

© 2021 The Author(s).

Keywords: GRP78; HBV S antigen; RPLP1; RPLP2; antiviral; chronic hepatitis B; functional cure; hepatitis B virus; host factors; nucleic acid polymers

Conflict of interest statement

All authors declare no competing interests.

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