Antiviral research最新文献

The Ebola virus, a filovirus, has been responsible for significant human fatalities since its discovery. Despite extensive research, effective small-molecule drugs remain elusive due to its complex pathogenesis. Inhibition of RNA synthesis is a promising therapeutic target, and the VP30 protein plays a critical role in this process. The interaction between VP30 and the nucleoprotein (NP) is essential for viral replication. We identified ginkgolic acid as a small molecule with strong affinity for VP30, which was validated through multiple assays, including thermal shift, surface plasmon resonance, fluorescence polarization, pull-down, and co-immunoprecipitation. The antiviral efficacy of ginkgolic acid was demonstrated in the EBOV transcription- and replication-competent virus-like particle (trVLP) system. Furthermore, we resolved the crystal structure of the VP30-ginkgolic acid complex, revealing two ginkgolic acid molecules located at the VP30/NP interaction interface. This structural information provides insight into the molecular basis of ginkgolic acid's antiviral activity and suggests a novel therapeutic strategy targeting the VP30/NP interaction.

The respiratory tract hosts a diverse microbial community whose composition varies with anatomical location and throughout life. Rothia mucilaginosa, a common commensal of the upper respiratory tract and oral cavity, has recently been recognized for its ability to inhibit bacteria-triggered pro-inflammatory responses. However, its role in modulating the immune response to viral infections such as influenza A virus (IAV) pneumonia, remains unknown. Here, we demonstrate that R. mucilaginosa enhances protection against IAV, promoting viral clearance, reducing inflammation, preserving bronchial and alveolar structures, and improving survival in a mouse model of influenza pneumonia. The enhanced viral clearance observed in R. mucilaginosa-treated mice is associated with the recruitment of innate immune cells to the lungs, including PD-L1-expressing neutrophils, alongside the production of the anti-inflammatory cytokine IL-10, both of which are known to play regulatory roles in the context of IAV infection. Together, these findings highlight R. mucilaginosa-mediated innate immune priming as a key protective mechanism in the respiratory tract against IAV infection.

Viral respiratory infection is associated with significant morbidity and mortality. The diversity of viruses implicated, coupled with their propensity for mutation, ignited an interest in host-directed antiviral therapies effective across a wide range of viral variants. Toll-like receptors (TLRs) are potential targets for the development of broad-spectrum antivirals given their central role in host immune defenses. Synthetic agonists of TLRs have been shown to boost protective innate immune responses against respiratory viruses. However, clinical success was hindered by short duration of benefit and/or induction of systemic adverse effects. INNA-051, a TLR2/6 agonist, is in development as an intranasal innate immune enhancer for prophylactic treatment in individuals at risk of complications resulting from respiratory viral infections. In vivo animal studies demonstrated the efficacy as prophylaxis against multiple viruses including SARS-CoV-2, influenza, and rhinovirus. Early clinical trials demonstrated an acceptable safety and tolerability profile. Intranasal delivery to the primary site of infection in humans induced a local innate host defense response characterized by innate immune cell infiltration into the nasal epithelium and activation and antiviral response genes. Taken together, the preclinical and clinical data on INNA-051 support further investigation of its use in community infection settings.

Background: Recent evidence has indicated that the O-glycosylated PreS2 domain of the middle HBsAg is a distinguishing characteristic that allows the identification of HBsAg of HBV Dane particles and SVPs. This study's objective was to assess the changes in serum O-glycosylated HBsAg levels in CHB patients undergoing ETV or Peg-IFNα treatment.

Methods: Our retrospective study enrolled 86 patients with genotype C CHB. We determined the O-glycosylated HBsAg, HBsAg, HBeAg, HBV DNA, and HBV RNA at baseline and during ETV or Peg-IFNα treatment. The correlations between O-glycosylated HBsAg and conventional HBV marker levels were also examined. Furthermore, we performed a ROC analysis to evaluate the predictive value of individual biomarkers for virological response.

Results: At baseline, the serum O-glycosylated HBsAg levels were significantly correlated with the HBsAg (r = 0.754), HBV DNA (r = 0.498), HBeAg (r = 0.404), and HBV RNA (r = 0.399) in HBeAg positive patients. O-glycosylated HBsAg decreased after antiviral therapy. Both O-glycosylated HBsAg and HBsAg were significantly correlated with serum HBV DNA as well as HBV RNA at baseline, while only O-glycosylated HBsAg still correlated with HBV RNA (r = 0.397) in DNA-undetectable patients after ETV therapy. O-glycosylated HBsAg was significantly correlated with HBV RNA (r = 0.846) in DNA-undetectable patients after Peg-IFNα therapy compared to that of HBsAg (r = 0.800).

Conclusion: Serum O-glycosylated HBsAg level decreased during anti-viral therapy and correlated well with conventional HBV markers in HBeAg positive genotype C patients, suggesting that it could be a potential monitoring biomarker in HBV DNA-suppressed patients.

Dengue virus (DENV) is a rapidly expanding infectious disease threat that causes an estimated 100 million symptomatic infections every year. A barrier to preventing DENV infections with traditional vaccines or prophylactic monoclonal antibody (mAb) therapies is the phenomenon of Antibody-Dependent Enhancement (ADE), wherein sub-neutralizing levels of DENV-specific IgG antibodies can enhance infection and pathogenesis rather than providing protection from disease. Fortunately, IgG is not the only antibody isotype capable of binding and neutralizing DENV, as DENV-specific IgA1 isotype mAbs can bind and neutralize DENV while without exhibiting any ADE activity. However, the development of IgA1-based mAb therapies is currently hindered by inefficient in vitro expression systems and the lack of saleable purification platforms. Accordingly, alternative delivery modalities are required to realize the therapeutic potential of IgA-based infectious-disease therapies. In this study we describe the development and optimization of a DENV-specific single-chain IgA construct that retains the desirable biological properties of the parental IgA mAb yet is compatible with efficient in vivo delivery with a novel/liver-tropic lipid nanoparticle. We propose that this platform is uniquely and exceptionally well suited for preventing and/or treating DENV infections and may have broad applicability in the greater infectious disease space in situations where the use of IgG isotype mAbs may be counterindicated.

Enterovirus A71 (EV-A71) is an important human pathogen and 'prototype pathogen' for studies of other Enteroviruses of pandemic potential. Understanding the biology of EV-A71 would inform generalizable strategies for antiviral drug, vaccine, and monoclonal antibody development. Such studies are accelerated by robust reagents to evaluate efficacy. Here, we describe and evaluate a suite of synthetic reporter constructs to accelerate EV-A71 research and therapeutic discovery. These constructs include replicons and infectious clones carrying luminescent and fluorescent reporter proteins. Among the reporters we tested were shorter luminescent and de novo-designed synthetic fluorescent proteins, which enhance genetic stability, reduce reporter gene loss and improve the utility of these reporters. This toolbox provides free access to robust and flexible assays for EV-A71 infection and replication through public repositories, promoting and accelerating open scientific discovery for this understudied emerging pathogen.

Global swine industry has long been severely affected by the periodic outbreaks of porcine epidemic diarrhea (PED), a deadly infectious disease in piglets caused by the porcine epidemic diarrhea virus (PEDV). Currently, available vaccines and antiviral drugs could not provide effective prevention and treatment of PEDV infection in pigs. In this study, Boesenbergia rotunda (B. rotunda) extract and its major bioactive flavonoid, pinostrobin, were demonstrated to exhibit remarkable anti-PEDV activities with EC₅₀ values of 0.33 ± 0.02 μg/ml and 2.71 ± 0.12 μM, and selectivity indices (SI) of 11.93 and > 184.55, respectively. Results based on a time-of-addition assay showed that pinostrobin blocked PEDV infection mainly at the early stages of infection. More specifically, pinostrobin reduced cell-cell fusion mediated by the viral spike protein, suggesting that the compound may target the virus fusion step. We also synthesized pinostrobin derivatives and explored the impact of pinostrobin structural features to the observed anti-PEDV activity. Results indicated the importance of the hydroxyl group and substituent on the phenyl ring. In summary, this study highlights the potential of B. rotunda extract and its bioactive compound, pinostrobin, as candidates for the development of antiviral drugs to more effectively control PEDV infection.

Serum HBV-RNA is proposed to be a circulating marker of cccDNA transcriptional activity in hepatocytes. The combination of tenofovir-disoproxil-fumarate (TDF) and pegylated-interferon-alpha-2a (pegIFN) with nucleic-acid polymer (NAP) treatment was associated with a relatively high rate of functional cure (FC) 48 weeks after discontinuation of all therapy. We aim to characterize HBV RNA kinetics under TDF and pegIFN ± NAP combination therapies. Forty participants with chronic HBV in the REP401 phase-II clinical trial received 48 weeks of triple combination therapy with NAPs, pegIFN, and TDF. For 20 participants, triple combination therapy (TDF + pegIFN + NAPs) followed 24 weeks of TDF. For 20 other participants, triple combination therapy followed 24 weeks of TDF monotherapy and 24 weeks of dual therapy (TDF + pegIFN). The Abbott RUO assay for HBV RNA (LLoQ = 1.65 logU/mL) was performed every 4 weeks. Previously unrecognized HBV RNA kinetic patterns were identified with dual/triple therapy including (i) no change (ii) an increase followed by a new elevated plateau (only under dual therapy) and (iii) a transient increase followed by a spontaneous decline. All participants establishing a new elevated HBV RNA plateau level experienced a subsequent monophasic decline following the introduction of NAPs. Failure to reach HBV RNA LLoQ by 16 weeks of triple therapy had a negative predictive value of 100% for FC. The median HBV RNA half-life for participants in the virological-rebound group was significantly (p = 0.01) longer than in the partial and FC groups (5.7 vs 2.7 weeks, respectively). Achieving partial/functional cure is associated with a shorter HBV RNA half-life, which could reflect faster inactivation of cccDNA transcriptional activity.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global public health crisis and continues to pose grave threats to human health. The efficacy of current vaccines and therapeutics is likely limited for future emerging strains due to the highly mutative nature of the virus, underscoring an urgent need for the development of new, potent antiviral agents. In this study, we report the design and synthesis of a series of novel 2'-deoxy-2'-spirooxetane-7-deazapurine nucleoside analogs as potential inhibitors of SARS-CoV-2 replication. Some of these compounds demonstrate potent antiviral activity, offering a potential new weapon for therapeutic intervention against the ever-evolving SARS-CoV-2 virus. Among the tested compounds, nucleoside analog 11q exhibited the most potent antiviral activity against SARS-CoV-2 in Vero E6 cells, with IC₅₀ values of 0.14 μM for the wild-type strain and 0.36 μM for the BA.5 strain. Notably, compound 11q exhibits up to nine times greater inhibitory activity against wild-type SARS-CoV-2 compared to Remdesivir and also possesses a superior selectivity index. These findings suggest that compound 11q is a highly promising lead candidate for future drug development aimed at combating SARS-CoV-2.