Identification of polymerized-albumin receptor domain in the pre-S2 region of hepatitis B virus surface antigen M protein

Itoh, Yoshio; Kuroda, Shinya; Miyazaki, Takahiro; Otaka, Sachiko; Fujisawa, Yukio

doi:10.1016/0168-1656(92)90100-n

Cited by 13 publications

(5 citation statements)

References 31 publications

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“…However, some viruses can evade RES effectively and finally infect target cells and tissues in vivo , namely by virus-derived stealth activity. Meanwhile, it was demonstrated that HBV could associates with monomeric human serum albumin (HSA) and polymerized-HSA[ 35 , 36 ] through the polymerized-albumin receptor (PAR) domain in the pre-S2 region (120-129 aa)[ 37 ]. When LPs displaying the PAR domain-containing peptide were intravenously injected into mice, they could recruit albumins on their surface and evade RES effectively (Takagi et al personal communication).…”

Section: Bnc As Nanocarriermentioning

confidence: 99%

Elucidation of the early infection machinery of hepatitis B virus by using bio-nanocapsule

Liu¹,

Somiya²,

Kuroda³

2016

WJG

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Currently, hepatitis B virus (HBV), upon attaching to human hepatocytes, is considered to interact first with heparan sulfate proteoglycan (HSPG) via an antigenic loop of HBV envelope S protein. Then, it is promptly transferred to the sodium taurocholate cotransporting polypeptide (NTCP) via the myristoylated N-terminal sequence of pre-S1 region (from Gly-2 to Gly-48, HBV genotype D), and it finally enters the cell by endocytosis. However, it is not clear how HSPG passes HBV to NTCP and how NTCP contributes to the cellular entry of HBV. Owing to the poor availability and the difficulty of manipulations, including fluorophore encapsulation, it has been nearly impossible to perform biochemical and cytochemical analyses using a substantial amount of HBV. A bio-nanocapsule (BNC), which is a hollow nanoparticle consisting of HBV envelope L protein, was efficiently synthesized in Saccharomyces cerevisiae. Since BNC could encapsulate payloads (drugs, genes, proteins) and specifically enter human hepatic cells utilizing HBV-derived infection machinery, it could be used as a model of HBV infection to elucidate the early infection machinery. Recently, it was demonstrated that the N-terminal sequence of pre-S1 region (from Asn-9 to Gly-24) possesses low pH-dependent fusogenic activity, which might play a crucial role in the endosomal escape of BNC payloads and in the uncoating process of HBV. In this minireview, we describe a model in which each domain of the HBV L protein contributes to attachment onto human hepatic cells through HSPG, initiation of endocytosis, interaction with NTCP in endosomes, and consequent provocation of membrane fusion followed by endosomal escape.

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Section: Bnc As Nanocarriermentioning

confidence: 99%

Elucidation of the early infection machinery of hepatitis B virus by using bio-nanocapsule

Liu¹,

Somiya²,

Kuroda³

2016

WJG

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“…A HBV mutant lacking PAR activity has been shown to lose its infectivity in chimpanzees, suggesting that PAR is involved in the HBV infection machinery [ 26 ]. Previously, our group delineated that the region responsible for PAR activity is between residues Leu-12 and Tyr-21 of the pre-S2 region [ 31 ]. Here, a peptide containing the putative PAR region (Leu-12 to Tyr-21; peptide 1), as well as a peptide encompassing the putative PAR region (Thr-7 to Ala-24; peptide 2), were synthesized ( Figure 4 A) and examined for their PAR activity by pull-down assays.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, when residue Tyr-21 of peptides 1 and 2 was replaced with Pro to generate peptides 3 and 4, respectively, peptide-conjugated resins were not able to interact with pHSA ( Figure 4 B) or to interfere with the interaction between BNCs and pHSA ( Figure 4 C). Since the PAR region was postulated to be located between two putative helixes (from Met-1 to Leu-13 and from Leu-20 to Phe-46) [ 31 ], the Pro-21 mutation might work as a breaker against the second helix and thereby affect the PAR function.…”

Section: Resultsmentioning

confidence: 99%

Polymerized Albumin Receptor of Hepatitis B Virus for Evading the Reticuloendothelial System

et al. 2021

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Various strategies, such as optimization of surface chemistry, size, shape, and charge, have been undertaken to develop nanoparticles (NPs) as DDS (drug delivery system) nanocarriers for evading the reticuloendothelial system (RES) in vivo. We previously developed a hollow NP composed of hepatitis B virus (HBV) surface antigen L proteins and lipid bilayers, hereinafter referred to as bio-nanocapsule (BNC), as a nonviral DDS nanocarrier. Such a BNC harbors the HBV-derived human hepatic cell-specific infection mechanism, and intravenously injected BNCs by themselves were shown to avoid clearance by RES-rich organs and accumulate in target tissues. In this study, since the surface modification with albumins is known to prolong the circulation time of nanomedicines, we examined whether the polymerized albumin receptor (PAR) of BNCs contributes to RES evasion in mouse liver. Our results show that NPs conjugated with peptides possessing sufficient PAR activity were captured by Kupffer cells less efficiently in vitro and were able to circulate for a longer period of time in vivo. Comparing with polyethylene glycol, PAR peptides were shown to reduce the recognition by RES to equal content. Taken together, our results strongly suggest that the PAR domain of BNCs, as well as HBV, harbors an innate RES evasion mechanism. Therefore, the surface modification with PAR peptides could be an alternative strategy for improving the pharmacodynamics and pharmacokinetics of forthcoming nanomedicines.

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“…The specific binding of human serum albumin to HBV surface proteins has been previously reported in several occasions [28–30], which eventually led to speculations about a possible role in serving as an intermediate receptor for viral infections of liver cells [31]. Further studies have narrowed down the pHSA‐binding site to the preS2 region within the HBsAg [28, 32], and have also shown that this interaction is species‐specific and does not occur with non‐primates serum albumin [17]. Nevertheless, it is still largely unknown how and in what way pHSA binds to the preS2 proteins, and what the biological consequences this observation might have in vivo .…”

Section: Discussionmentioning

confidence: 99%

Targeted destruction of the polymerized human serum albumin binding site within the preS2 region of the HBV surface antigen while retaining full immunogenicity for this epitope

Park¹,

Lee

Kim

et al. 2003

Journal of Viral Hepatitis

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The 55-amino acid (a.a.) preS2 region of the hepatitis B virus (HBV) envelope protein is highly immunogenic, and antibodies against this epitope confer seroprotection against HBV infections. Accordingly, various experimental and clinical studies for developing and evaluating HBV vaccines that include this particular epitope have been reported. However, a pitfall in using preS2 epitopes as part of a vaccinating antigen is that polymerized human serum albumin (pHSA), which is a normal constituent of the human serum, binds to and makes complexes with this particular region. Consequently, it is most likely that the antigen epitope is masked by serum pHSA and subsequently not detected by the immune system. To overcome these limitations, a novel single a.a substitute of the preS2 region was designed that corresponds to a tyrosine to serine exchange at position 140 of preS2. Competitive enzyme-linked immunosorbent assay showed that this substitution completely abolishes pHSA-binding activities in the mutated preS2 peptide, and CD spectra analysis revealed that this property might have been induced by slight conformational changes in its secondary structure. Nevertheless, the original B-cell epitope was still preserved in the mutated preS2 as determined by experimental immunization in mice. In this regard, the preS2(120-145/Y140S) sequence may be an HBV vaccine where epitopes, with intrinsic properties have been deleted without affecting the immunogenicity of the epitope itself. It is expected that the inclusion of this point mutated preS2 epitope will improve the efficacy of conventional preS2-containing HBV vaccines.

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Identification of polymerized-albumin receptor domain in the pre-S2 region of hepatitis B virus surface antigen M protein

Cited by 13 publications

References 31 publications

Elucidation of the early infection machinery of hepatitis B virus by using bio-nanocapsule

Elucidation of the early infection machinery of hepatitis B virus by using bio-nanocapsule

Polymerized Albumin Receptor of Hepatitis B Virus for Evading the Reticuloendothelial System

Targeted destruction of the polymerized human serum albumin binding site within the preS2 region of the HBV surface antigen while retaining full immunogenicity for this epitope

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