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

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-04 DOI:10.1016/j.bmcl.2024.130054

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

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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.

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基于病毒核心蛋白的肽基乙型肝炎病毒衣壳抑制剂的鉴定。

在这项研究中，我们从基于乙型肝炎病毒（HBV）核心蛋白系统设计的肽库中鉴定出两个抑制HBV衣壳组装的新肽，19Ac（包含残基91-105）和20Ac（包含残基96-110）。肽20Ac表现出约两倍于19Ac的抑制效力，并被证明对标准和morphothiadin （GLS4）耐药的HBV株都有效。分子动力学模拟显示，尽管19Ac和20Ac序列重叠，但它们与核心蛋白的不同区域结合，从而通过不同的机制抑制衣壳组装。这些肽可以作为有价值的种子化合物，用于进一步开发HBV衣壳抑制剂，包括gls4耐药菌株。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.

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