Kuancheng Liu

Functional cure, defined as sustained hepatitis B surface antigen (HBsAg) loss, remains a major goal in chronic hepatitis B (CHB) management. HBsAg kinetics during interferon (IFN)-based therapy are associated with treatment response and prognosis, but real-world data on weekly HBsAg dynamics remain limited. This retrospective real-world study enrolled 533 CHB patients treated with IFN monotherapy or IFN plus tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), or entecavir (ETV). Weekly HBsAg levels up to week 24 were analyzed using propensity score matching (PSM), subgroup analyses, and generalized estimating equations (GEEs). HBsAg kinetics showed marked heterogeneity, with some patients exhibiting transient early increases. Lower baseline HBsAg levels and rapid early decline were strongly associated with HBsAg loss. After PSM, IFN monotherapy and combination therapy showed comparable HBsAg decline trajectories. The three NA regimens demonstrated similar overall kinetics, although subgroup differences were observed by sex, immune activity, HBV DNA status, and prior treatment. TDF showed a faster decline in females, whereas ETV declined faster in males and immune-active patients. In conclusion, HBsAg kinetics during IFN-based therapy are highly heterogeneous and mainly influenced by baseline HBsAg levels, early on-treatment decline, and host factors. Weekly HBsAg monitoring may help predict treatment response and guide individualized CHB management.

Current HBV treatment with nucleos(t)ide analogs requires lifelong administration and is associated with the risk of drug resistance, underscoring the urgent need for novel antivirals with alternative targets. Herein, we reported the design, synthesis, and biological evaluation of a series of salicylamide derivatives as potent anti-HBV agents. The nine selected compounds exhibited dose-dependent inhibitory effects on HBV replication, as evidenced by significant reductions in both virion DNA and the secretion levels of HBsAg and HBeAg. Among them, compounds 50 and 56 exhibited the highest anti-HBV activity (IC₅₀ = 0.52 and 0.47 μM, respectively) and selectivity (SI = 20.1 and 17.6, respectively). Mechanistic studies revealed that compounds 27, 31, and 47 impaired HBV core protein (HBc) expression, while compound 50 disrupted capsid formation without significantly affecting HBc expression. These findings highlight the therapeutic potential of salicylamide derivatives as promising anti-HBV agents and provide a foundation for further structural optimization and mechanistic exploration.

Coronavirus infectious disease 2019 (COVID-19), caused by severe acute respiratory virus type 2 (SARS-CoV-2), has caused a global public health crisis. As an RNA virus, the high gene mutability of SARS-CoV-2 poses significant challenges to the development of broad-spectrum vaccines and antiviral therapeutics. There remains a lack of specific therapeutics directly targeting SARS-CoV-2. With the ability to efficiently inhibit the expression of target genes in a sequence-specific way, small interfering RNA (siRNA) therapy has exhibited significant potential in antiviral and other disease treatments. In this work, we presented a highly effective self-assembled siRNA nanoparticle targeting multiple highly conserved regions of SARS-CoV-2. The siRNA sequences targeting viral conserved regions were first screened and evaluated by their thermodynamic features, off-target effects, and secondary structure toxicities. RNA motifs including siRNA sequences were then designed and self-assembled into siRNA nanoparticles. These siRNA nanoparticles demonstrated remarkable uniformity and stability and efficiently entered cells directly through cellular endocytic pathways. Moreover, these nanoparticles effectively inhibited the replication of SARS-CoV-2, exhibiting a superior inhibitory effect compared to free siRNA. These results demonstrated that these self-assembled siRNA nanoparticles targeting highly conserved regions of SARS-CoV-2 represent highly effective antiviral candidates for the treatment of infections, and are promisingly effective against current and future viral variants.

Tick‐borne orthonairoviruses have been characterized as a global health threat to humans and animals. Tacheng Tick virus 1 (TcTV‐1) from this family was provided as evidence that is associated with the febrile illness syndrome. Here, we first identify and demonstrate that the ovarian tumor (OTU) domain of TcTV‐1 has remarkable deubiquitinating activity both in vitro and in vivo. By solving the crystal structure of TcTV‐1 OTU (tcOTU) domain and comparing it to that of human deubiquitinating enzymes, we found that overall structures of tcOTU and human OTU family are similar, but the residues involved in the catalytic pocket vary widely. Based on the tcOTU domain we screened 5090 bioactive compounds and found mecobalamin had a good effect on suppressing the deubiquitinating activity. The structural model of tcOTU and mecobalamin suggests that mecobalamin occupies the site of the substrate Ub, by blocking the substrate binding to the enzyme. Thus, our results showed OTU domain of TcTV‐1 has a robust deubiquitinating activity and mecobalamin or its derivatives might be promising candidates for the treatment or prevention of disease caused by the TcTV‐1 virus.

Chronic hepatitis B virus (HBV) infection is an important public health problem. Polygonum perfoliatum L. is a traditional medicinal herb and has been reported to have pharmacological activities such as anti‐inflammatory, antibacterial, and antiviral. In this study, the antiviral activities and mechanisms of Polygonum perfoliatum L. extract against HBV and the effective components were investigated. The results showed that the total extract of Polygonum perfoliatum L. reduced the levels of HBV e antigen (HBeAg) secretion and the viral covalently closed circular DNA (CCC DNA) formation, but had little or no negative effects on viral capsid assembly and pregenomic RNA packaging. Further fractionation showed that the water extract (WE) fraction exerted comparable anti‐HBV activities with the total extract, especially in inhibiting the CCC DNA formation and HBeAg production, indicating that the effective antiviral components are mainly distributed in this fraction. Further study showed that the phenolic acids constituents, protocatechuic acid, and gallic acid, but not ethyl caffeate, which is reported enriched in the WE fraction, showed strong anti‐HBV activities in inhibiting viral core DNA synthesis, CCC DNA formation, and HBeAg production. These results suggested that the Polygonum perfoliatum L. total extract and the related phenolic acids like protocatechuic acid and gallic acid could inhibit HBV replication and also indicated the potential utility of Polygonum perfoliatum L. and related constituents as sources of novel antivirals against HBV.

Disassembly of the hepatitis B virus (HBV) nucleocapsid (NC) to release its genomic DNA, in an ill-understood process called uncoating, is required to form the viral nuclear episome in the host cell nucleus, a viral DNA essential for establishing and sustaining HBV infection. The elimination of the HBV nuclear episome remains the holy grail for the development of an HBV cure.

The chronic hepatitis B virus (HBV) infection is a worldwide public health problem, which cannot be cured by current therapeutics due to the persistence of viral CCC DNA in the infected hepatocytes. Screening from medicinal herbs for anti-HBV activities showed that the ethanol extract from Ranunculus japonicus Thunb. could decrease the production of HBV e antigen (HBeAg). Further study showed that the extract had no effect on core protein expression but significantly reduced the efficiency of viral capsid assembly. The levels of viral pgRNA and total core DNA were not affected significantly. However, the ratio of RC DNA/SS DNA decreased, indicating that the conversion of RC DNA from SS DNA was delayed by the extract. More interestingly, though similar levels of RC DNA were accumulated, the CCC DNA level and its formation efficiency were reduced significantly, which was also consistent with the decreased level of HBeAg, indicating that Ranunculus japonicus Thunb. extract could inhibit the CCC DNA formation. Together, this study found that Ranunculus japonicus Thunb. extract could inhibit HBV replication at multiple steps, especially showed significant inhibitory effects on capsid assembly and CCC DNA formation.