Abstract
Entry inhibitors are promising novel antivirals against hepatitis B virus (HBV) infection. The existing potential entry inhibitors have targeted the cellular receptor(s). In this study, we aim to develop the first entry inhibitor that inhibits HBV infection via targeting viral particles. The preS1 segment of the large envelope glycoprotein of HBV is essential for virion attachment and infection. Previously, we obtained a preS1-binding short peptide B10 by screening a phage display peptide library using the N-terminal half of preS1 (residues 1 to 60, genotype C). We report here that by means of concatenation of B10, we identified a quadruple concatemer 4B10 that displayed a markedly increased preS1-binding activity. The main binding site of 4B10 in preS1 was mapped to the receptor binding enhancing region. 4B10 blocked HBV attachment to hepatic cells and inhibited HBV infection of primary human and tupaia hepatocytes at low nanomolar concentrations. The 4B10-mediated inhibition of HBV infection is specific as it did not inhibit the infection of vesicular stomatitis virus glycoprotein pseudotyped lentivirus or human immunodeficiency virus type 1. Moreover, 4B10 showed no binding activity to hepatic cells. In conclusion, we have identified 4B10 as a promising candidate for a novel class of HBV entry inhibitors.
Highlights
More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV)[1]
The hepato-tropism is partially attributed to the entry step that presumably begins with reversible, low-affinity attachment of HBV to cell membrane via the interaction between viral envelope proteins and heparan sulfate proteoglycan (HSPG), followed by high-affinity binding of viral envelope proteins to a specific receptor(s) such as the bile-acid pump sodium-taurocholate cotransporting polypeptide (NTCP)[6,7,8]
Myrcludex B, a synthetic N-myristoylated peptide composed of the residues from 2 to 48 of preS1 that harbors the putative receptor binding region could effectively block HBV entry into HepaRG cells, primary tupaia hepatocytes (PTH) and primary human hepatocytes (PHH), as well as inhibit HBV infection in animal models[12,13,14]
Summary
More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV)[1]. The hepato-tropism is partially attributed to the entry step that presumably begins with reversible, low-affinity attachment of HBV to cell membrane via the interaction between viral envelope proteins and heparan sulfate proteoglycan (HSPG), followed by high-affinity binding of viral envelope proteins to a specific receptor(s) such as the bile-acid pump sodium-taurocholate cotransporting polypeptide (NTCP)[6,7,8]. Myrcludex B, a synthetic N-myristoylated peptide composed of the residues from 2 to 48 of preS1 (preS1/2-48myr, genotype D) that harbors the putative receptor binding region could effectively block HBV entry into HepaRG cells, primary tupaia hepatocytes (PTH) and primary human hepatocytes (PHH), as well as inhibit HBV infection in animal models[12,13,14]. The high inhibitory efficacy of 4B10 on HBV infection makes the peptide a promising candidate for a novel class of HBV entry inhibitors
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