Medicinal Chemistry Research

, Volume 26, Issue 11, pp 2824–2831 | Cite as

Structure-based rational design of peptide inhibitors to disrupt the recognition and interaction between hepatitis B virus large envelope protein and human hepatocyte receptor γ2-adaptin

  • Kuifeng Wang
  • Chunying Yang
  • Gang Lin
  • Gengge Wang
  • Jiansheng Zhu
Original Research


The virion escaping of hepatitis B virus from human hepatocyte is mediated by the recognition and interaction of viral large envelope protein with human hepatocyte receptor γ2-adaptin. In this work, a structure-based rational strategy was described to design peptide inhibitors serving as the interaction disruptors between the preS1 domain of hepatitis B virus large envelope protein and the EAR domain of γ2-adaptin. The binding site of preS1 to γ2-EAR was extracted from the crystal structure of preS1 in complex with EAR as a short preS129–36 phage peptide that can extendedly bind on the β-sheet surface of γ2-EAR domain. Computational modeling revealed a systematic amino acid preference profile for the domain–peptide interaction, which was then employed to guide an optimization protocol for improving the biological activity of preS129–36 peptide. A number of potential hits were obtained from the evolution, and four were measured in vitro to have a comparable or higher affinity as compared to the native preS129–36 peptide. Potent peptide ligands were structurally optimized according to alanine-scanning mutagenesis and complex structural analysis, resulting in the strongest binder with domain-binding affinity at micromolar level. It is revealed that a potent γ2-EAR-binding peptide (8-mer sequence X1X2X3X4X5X6X7X8) can be divided into three regions; the region 1 contains residues X2 and X3 that should be occupied by negatively charged amino acids such as Glu and Asp, the region 2 covers residues X4, X5, and X6 that directly contact a hydrophobic pocket on γ2-EAR surface, and the region 3 corresponds to residue X7 that prefers polar amino acids and is able to form hydrogen bond. In addition, the N-terminal and C-terminal residues X1 and X8 only play a marginal role in the domain–peptide binding.


Hepatitis B virus Human hepatocyte receptor Rational drug design Structural bioinformatics 



This work was supported by the Natural Science Foundation of Zhejiang Province (No. LY15H030003) and the Zhejiang Province Major Science and Technology Programs (No. 2012C13018-3).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Infectious DiseasesTaizhou Central HospitalZhejiangChina
  2. 2.Department of Infectious DiseasesThe Affiliated Taizhou Hospital of Wenzhou Medical UniversityTaizhouChina

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