Hepatitis B virus peptide inhibitors: solution structures and interactions with the viral capsid

Abstract

Hepatitis B virus (HBV) infection remains a health problem globally despite the availability of effective vaccines. In the assembly of the infectious virion, both the preS and S regions of the HBV large surface antigen (L-HBsAg) interact synergistically with the viral core antigen (HBcAg). Peptides preS and S based on the L-HBsAg were demonstrated as potential inhibitors to block the viral assembly. Therefore, the objectives of this study were to determine the solution structures of these peptides and study their interactions with HBcAg. The solution structures of these peptides were solved using (1)H, (13)C, and (15)N NMR spectroscopy. Peptide preS has several structured regions of β-turns at Ser7-Pro8-Pro9, Arg11-Thr12-Thr13 and Ser22-Thr23-Thr24 sequences whereas peptide S has only one structured region observed at Ser3-Asn4-His5. Both peptides contain bend-like structures surrounding the turn structures. Docking studies revealed that both peptides interacted with the immunodominant region of HBcAg located at the tip of the viral capsid spikes. Saturation Transfer Difference (STD) NMR experiments identified several aromatic residues in peptides preS and S that interact with HBcAg. This study provides insights into the contact regions of L-HBsAg and HBcAg at atomic resolution which can be used to design antiviral agents that inhibit HBV morphogenesis.

In-silico design and molecular docking evaluation of peptides derivatives from bacteriocins and porcine beta defensin-2 as inhibitors of Hepatitis E virus capsid protein

“…In other viral models, synthetic peptides with coiled conformation designed to interact with Hepatitis B core antigen, inhibited a crucial step in Hepatitis B virus morphogenesis, blocking binding of the envelope surface antigen to the core antigen with an IC 50 of 30 lM [30], and similar to our results, where the best docking interaction occurred between subti1, a coiled peptide, and the target protein and where the interaction were also mediated mainly by S and R residues. Likewise, antiviral peptides designed using as models the N-term and C-term sequences of Influenza A Virus hemagglutinin displayed in vitro antiviral activity against different strains of Influenza A virus and the interaction between the designed peptides and the viral hemagglutinin was demonstrated by molecular docking strategies [28].…”

Conformational Plasticity of Hepatitis B Core Protein Spikes Promotes Peptide Binding Independent of the Secretion Phenotype

“…Therefore, it is likely that HBs and peptides compete for the same binding site. Docking of NMR structures of binding fragments derived from L-HBs and S-HBs suggests that they bind to the tips of the spikes in the open conformation with the splayed loops [ 53 , 55 ] as P2 does. The pocket in the center of the spike is too small to accommodate peptide binders or the binding site of HBs directly.…”

Peptides to combat viral infectious diseases

“…HBV is an enveloped virus that is coated with a lipid bilayer and packaged with viral polymerase, relaxed circular DNA (rcDNA), and three types of antigens: surface antigen (HBsAg), e antigen (HBeAg), and core antigen (HBcAg). Upon infection, rcDNA is converted into the host-specific covalently closed circular DNA (cccDNA) by the viral polymerase, which plays a critical role in HBV replication [ 165 , 146 , 75 ].…”

“…This topological change allows HBV to become a "binder-type particle" and recognizes the receptors on the host cells [ 165 , 206 ]. Three β-turn structures in pre-S1 and one in S region were identified by NMR spectroscopy as critical regions for this process [ 146 ]. Although additional work is needed, this finding provided a new strategy for designing inhibitors that might prevent the conformational change in the pre-S domain and interrupt the HBV morphogenesis.…”