Identification of peptide-based hepatitis B virus capsid inhibitors based on the viral core protein

Junko Fujimoto; Kazutoshi Kawahara; Kazuma Takeda; Sayuri Takeo; Kohei Sato; Kenji Nakashima; Nobuyuki Mase; Masaru Yokoyama; Tetsuro Suzuki; Tetsuo Narumi

doi:10.1016/j.bmcl.2024.130054

Identification of peptide-based hepatitis B virus capsid inhibitors based on the viral core protein

Bioorg Med Chem Lett. 2024 Dec 4:117:130054. doi: 10.1016/j.bmcl.2024.130054. Online ahead of print.

Authors

Affiliations

¹ Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan.
² Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan.
³ Graduate School of Medical Photonics, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan.
⁴ Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Research Institute of Green Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan.
⁵ Department of Microbiology and Immunology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, Japan.
⁶ Pathogen Genomics Center, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo, Japan.
⁷ Department of Applied Chemistry and Biochemical Engineering, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Department of Engineering, Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Graduate School of Medical Photonics, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan; Research Institute of Green Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan. Electronic address: [email protected].

PMID: 39643018
DOI: 10.1016/j.bmcl.2024.130054

Abstract

In this study, we have identified two novel peptides, 19Ac (comprising residues 91-105) and 20Ac (encompassing residues 96-110), from a systematically designed peptide library based on the Hepatitis B virus (HBV) core protein, that inhibit the assembly of HBV capsid. Peptide 20Ac exhibited about twofold the inhibitory potency of 19Ac and proved effective against both standard and morphothiadin (GLS4)-resistant HBV strains. Molecular dynamics simulations revealed that despite their overlapping sequence, 19Ac and 20Ac bonded to different regions of the core protein, thereby inhibiting capsid assembly through distinct mechanisms. These peptides could serve as valuable seed compounds for the further development of HBV capsid inhibitors, including GLS4-resistant strains.

Keywords: Capsid assembly inhibitors; Hepatitis B virus (HBV); Molecular dynamics simulations; Peptide library screening.