Antiviral Research

Currently, there are two approved vaccine regimens designed to prevent Ebola virus (EBOV) disease (EVD). Both are virus-vectored, and concerns about cold-chain storage and pre-existing immunity to the vectors warrant investigating additional vaccine strategies. Here, we have explored the utility of adjuvanted recombinant glycoproteins (GPs) from ebolaviruses Zaire (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) for inducing antibody (Ab) and T cell cross-reactivity. Glycoproteins expressed in insect cells were administered to C57BL/6 mice as free protein or bound to the surface of liposomes, and formulated with toll-like receptor agonists CpG and MPLA (agonists for TLR 9 and 4, respectively), with or without the emulsions AddaVax or TiterMax...

The emerging SARS-CoV-2 variants are evolving to evade human immunity and differ in their pathogenicity. While evasion of the variants from adaptive immunity is widely investigated, there is a paucity of knowledge about their interactions with innate immunity. Inflammasome assembly is one of the most potent mechanisms of the early innate response to viruses, but when it is inappropriate, it can perpetuate tissue damage. In this study, we focused on the capacity of SARS-CoV-2 Alpha and Delta variants to activate the NLRP3 inflammasome...

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with frequent mutations has seriously damaged the effectiveness of the 2019 coronavirus disease (COVID-19) vaccine. There is an urgent need to develop a broad-spectrum vaccine while elucidating the underlying immune mechanisms. Here, we developed a SARS-CoV-2 virus-like particles (VLPs) vaccine based on the Canarypox-virus vector (ALVAC-VLPs) using CRISPR/Cas9. Immunization with ALVAC-VLPs showed the effectively induce SARS-CoV-2 specific T and B cell responses to resist the lethal challenge of mouse adaptive strains...

Four years after its outbreak, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a global challenge for human health. At its surface, SARS-CoV-2 features numerous extensively glycosylated spike proteins. This glycan coat supports virion docking and entry into host cells and at the same time renders the virus less susceptible to neutralizing antibodies. Given the high genetic plasticity of SARS-CoV-2 and the rapid emergence of immune escape variants, targeting the glycan shield by carbohydrate-binding agents emerges as a promising strategy...

Host targeting antiviral drugs (HTA) are directed against cellular mechanisms which can be exploited by viruses. These mechanisms are essential for viral replication, because missing functions cannot be compensated by the virus. However, this assumption needs experimental proof. Here we compared the HTA Zapnometinib (ZMN), with direct acting antivirals (DAA) (Remdesivir (RDV), Molnupiravir (MPV), Nirmatrelvir (NTV), Ritonavir (RTV), Paxlovid PAX)), in terms of their potency to induce reduced drug susceptibilities in SARS-CoV-2...

While clinical trials have illuminated both the virological and clinical efficacy of baloxavir for influenza and post-treatment viral resistance, these aspects warrant further study in real-world settings. In response, we executed a prospective, observational study of the Japanese 2022-2023 influenza season. A cohort of 73 A(H3N2)-diagnosed outpatients-36 treated with baloxavir, 20 with oseltamivir, and 17 with other neuraminidase inhibitors (NAIs)-were analyzed. Viral samples were collected before and after administering an antiviral on days 1, 5, and 10, respectively...

The Third International Conference on Crimean-Congo Hemorrhagic Fever (CCHF) was held in Thessaloniki, Greece, September 19-21, 2023, bringing together a diverse group of international partners, including public health professionals, clinicians, ecologists, epidemiologists, immunologists, and virologists. The conference was attended by 118 participants representing 24 countries and the World Health Organization (WHO). Meeting sessions covered the epidemiology of CCHF in humans; Crimean-Congo hemorrhagic fever virus (CCHFV) in ticks; wild and domestic animal hosts; molecular virology; pathogenesis and animal models; immune response related to therapeutics; and CCHF prevention in humans...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological cause of coronavirus disease 2019 (COVID-19) and continues to be a major health concern worldwide. Strategies to protect individuals at high risk of COVID-19 are critical but are currently a largely unmet need. We evaluated the oral antiviral drug ensitrelvir, which specifically targets the SARS-CoV-2 3CL protease, for its efficacy as a pre-exposure prophylactic treatment. Aged BALB/c mice were subcutaneously treated with various doses of ensitrelvir 24 h prior to a lethal SARS-CoV-2 challenge infection...

Enteroviruses are a significant global health concern, causing a spectrum of diseases from the common cold to more severe conditions like hand-foot-and-mouth disease, meningitis, myocarditis, pancreatitis, and poliomyelitis. Current treatment options for these infections are limited, underscoring the urgent need for effective therapeutic strategies. To find better treatment option we analyzed efficacy of 12 known broad-spectrum anti-enterovirals both individually and in combinations against different enteroviruses in vitro...

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been ongoing for more than three years and urgently needs to be addressed. Traditional Chinese medicine (TCM) prescriptions have played an important role in the clinical treatment of patients with COVID-19 in China. However, it is difficult to uncover the potential molecular mechanisms of the active ingredients in these TCM prescriptions. In this paper, we developed a new approach by integrating the experimental assay, virtual screening, and the experimental verification, exploring the rapid discovery of active ingredients from TCM prescriptions...

Nucleic acid polymers (NAPs) are an attractive treatment modality for chronic hepatitis B (CHB), with REP2139 and REP2165 having shown efficacy in CHB patients. A subset of patients achieve functional cure, whereas the others exhibit a moderate response or are non-responders. NAP efficacy has been difficult to recapitulate in animal models, with the duck hepatitis B virus (DHBV) model showing some promise but remaining underexplored for NAP efficacy testing. Here we report on an optimized in vivo DHBV duck model and explore several characteristics of NAP treatment...

The COVID-19 pandemic has shown the need to develop effective therapeutics in preparedness for further epidemics of virus infections that pose a significant threat to human health. As a natural compound antiviral candidate, we focused on α-dystroglycan, a highly glycosylated basement membrane protein that links the extracellular matrix to the intracellular cytoskeleton. Here we show that the N-terminal fragment of α-dystroglycan (α-DGN), as produced in E. coli in the absence of post-translational modifications, blocks infection of SARS-CoV-2 in cell culture, human primary gut organoids and the lungs of transgenic mice expressing the human receptor angiotensin I-converting enzyme 2 (hACE2)...

Rabies, a viral zoonosis, is responsible for almost 59,000 deaths each year, despite the existence of an effective post-exposure prophylaxis. Indeed, rabies causes acute encephalomyelitis, with a case-fatality rate of 100 % after the onset of neurological clinical signs. Therefore, the development of therapies to inhibit the rabies virus (RABV) is crucial. Here, we identified, from a 30,000 compound library screening, phthalazinone derivative compounds as potent inhibitors of RABV infection and more broadly of Lyssavirus and even Mononegavirales infections...

Human norovirus (HuNoV) and human rotavirus (HRV) are the leading causes of gastrointestinal diarrhea. There are no approved antivirals and rotavirus vaccines are insufficient to cease HRV associated mortality. Furthermore, treatment of chronically infected immunocompromised patients is limited to off-label compassionate use of repurposed antivirals with limited efficacy, highlighting the urgent need of potent and specific antivirals for HuNoV and HRV. Recently, a major breakthrough in the in vitro cultivation of HuNoV and HRV derived from the use of human intestinal enteroids (HIEs)...

Neutralizing antibodies (NAbs) are naturally produced by our immune system to combat viral infections. Clinically, neutralizing antibodies with potent efficacy and high specificity have been extensively used to prevent and treat a wide variety of viral infections, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Human Immunodeficiency Virus (HIV), Dengue Virus (DENV) and Hepatitis B Virus (HBV). An overwhelmingly large subset of clinically effective NAbs operates by targeting viral envelope proteins to inhibit viral entry into the host cell...

Foot-and-mouth disease (FMD) is an economically important disease, and the FMD virus (FMDV) can spread rapidly in susceptible animals. FMD is usually controlled through vaccination. However, commercial FMD vaccines are only effective 4-7 days after vaccination. Furthermore, FMDV comprises seven serotypes and various topotypes, and these aspects should be considered when selecting a vaccine. Antiviral agents could provide rapid and broad protection against FMDV. Therefore, this study aimed to develop a consensus porcine interferon-α (IFN-α) and Fc portion of porcine antibody IgG fusion protein (poIFN-α-Fc) using a baculovirus expression system to develop a novel antiviral agent against FMDV...

Influenza therapeutics with new targets and modes of action are urgently needed due to the frequent emergence of mutants resistant to currently available anti-influenza drugs. Here we report the in vitro and in vivo anti-influenza A virus activities of cyperenoic acid, a natural compound, which was isolated from a Chinese medicine Croton crassifolius Geise. Cyperenoic acid could potently suppress H1N1, H3N2 and H9N2 virus replication with IC50 values ranging from 0.12 to 15.13 μM, and showed a low cytotoxicity against MDCK cells (CC50  = 939...

Mucosal immunity has regained its spotlight amidst the ongoing Coronavirus Disease 19 (COVID-19) pandemic, with numerous studies highlighting the crucial role of mucosal secretory IgA (SIgA) in protection against SARS-CoV-2 infections. The observed limitations in the efficacy of currently authorized COVID-19 vaccines in inducing effective mucosal immune responses remind us of the limitations of systemic vaccination in promoting protective mucosal immunity. This resurgence of interest has motivated the development of vaccine platforms capable of enhancing mucosal responses, specifically the SIgA response, and the development of IgA-based therapeutics...

The Hepatitis B Virus (HBV) ribonuclease H (RNase H) although promising remains an unexploited therapeutic target. HBV RNase H inhibition causes premature termination of viral minus-polarity DNA strands, prevents the synthesis of the viral positive-polarity DNA strand, and causes accumulation of RNA:DNA heteroduplexes within viral capsids. As part of our ongoing research to develop more potent anti-HBV RNase H inhibitors, we designed, synthesized and analyzed a library of 18 novel compounds (17 N-hydroyxpyridinedione (HPD) imine derivatives and 1 barbituric acid analogue) as potential leads for HBV treatment development...

Feline coronavirus (FCoV) is an unsegmented, single-stranded RNA virus belonging to the Alphacoronavirus genus. It can cause fatal feline infectious peritonitis (FIP) in cats of any ages. Currently, there are no effective prevention and control measures to against FCoV. In this study, we developed a recombinant adenovirus vaccine, AD5-N, based on the nucleocapsid(N) protein of FCoV. The immunogenicity of AD5-N was evaluated through intramuscular immunization in 6-week-old Balb/c mice and 9-12 months old cats...