Approved Antiviral Drugs Research Articles

Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells

Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions.Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model.Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches.In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D.

5-Bromo-2′-deoxyuridine inhibits African swine fever virus (ASFV) replication via interfering viral DNA replication and suppressing the formation of viral factories

African swine fever (ASF), caused by ASF virus (ASFV), represents one of the most economically important viral infectious diseases in swine industry worldwide. So far there is no vaccine or antiviral drug for controlling ASF pandemics. In the present study, we assessed inhibition of six nucleoside analogues against ASFV replication in ex vivo primary porcine alveolar macrophages (PAMs), including the first approved antiviral drug idoxuridine. Our results showed that, out of the assessed six compounds, 5-Bromo-2′-Deoxyuridine (5-BrdU, an analog of idoxuridine), exhibited the strongest inhibition on the replication of ASFV in PAMs with a 50% inhibitory concentration (IC50) value of 2.9 μM and a low cytotoxicity (CC50 > 270 μM). Moreover, we showed that 5-BrdU interferes with ASFV DNA replication by incorporating into viral replicating DNA molecules as a competitive substrate for deoxythymidine, ultimately inhibiting the formation of ASFV viral factories. Altogether, our findings suggest that 5-BrdU could serve as a promising therapeutic agent for combating ASFV infection.

An attachment glycoprotein nanoparticle elicits broadly neutralizing antibodies and protects against lethal Nipah virus infection

Nipah virus (NiV) is a zoonotic emergent paramyxovirus that can cause severe encephalitis and respiratory infections in humans, with a high fatality rate ranging from 40% to 75%. Currently, there are no approved human vaccines or antiviral drugs against NiV. Here, we designed a ferritin-based self-assembling nanoparticle displaying the NiV G head domain on the surface (NiV G-ferritin) and assessed immune responses elicited by the soluble NiV G head domain (NiV sG) or NiV G-ferritin. Immunization with NiV G-ferritin or NiV sG conferred complete protection against lethal NiV challenge without detection of viral RNA in Syrian golden hamsters. Compared to NiV sG, NiV G-ferritin induced significantly faster, broader, and higher serum neutralizing responses against three pathogenic henipaviruses (NiV-Malaysia, NiV-Bangladesh, and Hendra virus). Moreover, NiV G-ferritin induced a durable neutralizing immunity in mice as antisera potently inhibited NiV infection even after six months of the third immunization. Additionally, we isolated a panel of 27 NiV G-binding monoclonal antibodies (mAbs) from NiV G-ferritin immunized mice and found that these mAbs targeted four distinct antigenic sites on NiV G head domain with two sites that have not been defined previously. Notably, 25 isolated mAbs have potent neutralizing activity with 50% inhibitory concentrations less than 10 ng/mL against NiV pseudovirus. Collectively, these findings provide new insights into the immunogenicity of NiV G protein and reveal that NiV G-ferritin is a safe and highly effective vaccine candidate against Nipah virus infection.

Hexestrol, an estrogen receptor agonist, inhibits Lassa virus entry.

Lassa virus (LASV) is the causative agent of human Lassa fever which in severe cases manifests as hemorrhagic fever leading to thousands of deaths annually. However, no approved vaccines or antiviral drugs are currently available. Recently, we screened approximately 2,500 compounds using a recombinant vesicular stomatitis virus (VSV) expressing LASV glycoprotein GP (VSV-LASVGP) and identified a P-glycoprotein inhibitor as a potential LASV entry inhibitor. Here, we show that another identified candidate, hexestrol (HES), an estrogen receptor agonist, is also a LASV entry inhibitor. HES inhibited VSV-LASVGP replication with a 50% inhibitory concentration (IC50) of 0.63 µM. Importantly, HES also inhibited authentic LASV replication with IC50 values of 0.31 µM-0.61 µM. Time-of-addition and cell-based membrane fusion assays suggested that HES inhibits the membrane fusion step during virus entry. Alternative estrogen receptor agonists did not inhibit VSV-LASVGP replication, suggesting that the estrogen receptor itself is unlikely to be involved in the antiviral activity of HES. Generation of a HES-resistant mutant revealed that the phenylalanine at amino acid position 446 (F446) of LASVGP, which is located in the transmembrane region, conferred resistance to HES. Although mutation of F446 enhanced the membrane fusion activity of LASVGP, it exhibited reduced VSV-LASVGP replication, most likely due to the instability of the pre-fusion state of LASVGP. Collectively, our results demonstrated that HES is a promising anti-LASV drug that acts by inhibiting the membrane fusion step of LASV entry. This study also highlights the importance of the LASVGP transmembrane region as a target for anti-LASV drugs.IMPORTANCELassa virus (LASV), the causative agent of Lassa fever, is the most devastating mammarenavirus with respect to its impact on public health in West Africa. However, no approved antiviral drugs or vaccines are currently available. Here, we identified hexestrol (HES), an estrogen receptor agonist, as the potential antiviral candidate drug. We showed that the estrogen receptor itself is not involved in the antiviral activity. HES directly bound to LASVGP and blocked membrane fusion, thereby inhibiting LASV infection. Through the generation of a HES-resistant virus, we found that phenylalanine at position 446 (F446) within the LASVGP transmembrane region plays a crucial role in the antiviral activity of HES. The mutation at F446 caused reduced virus replication, likely due to the instability of the pre-fusion state of LASVGP. These findings highlight the potential of HES as a promising candidate for the development of antiviral compounds targeting LASV.

Design of multi-epitope chimeric vaccine against Monkeypox virus and SARS-CoV-2: A vaccinomics perspective.

The current era we experience is full with pandemic infectious agents that no longer threatens the major local source but the whole globe. Almost the most emerging infectious agents are severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), followed by monkeypox virus (MPXV). Since no approved antiviral drugs nor licensed active vaccines are yet available, we aimed to utilize immunoinformatics approach to design chimeric vaccine against the two mentioned viruses. This is the first study to deal with design divalent vaccine against SARS-CoV-2 and MPXV. ORF8, E and M proteins from Omicron SARS-CoV-2 and gp182 from MPXV were used as the protein precursor from which multi-epitopes (inducing B-cell, helper T cells, cytotoxic T cells and interferon-ɣ) chimeric vaccine was contrived. The structure of the vaccine construct was predicted, validated, and docked to toll-like receptor-2 (TLR-2). Moreover, its sequence was also used to examine the immune simulation profile and was then inserted into the pET-28a plasmid for in silico cloning. The vaccine construct was probable antigen (0.543) and safe (non-allergen) with strong binding energy to TLR-2 (-1169.8 kcal/mol) and found to have significant immune simulation profile. In conclusion, the designed chimeric vaccine was potent and safe against SARS-CoV-2 and MPXV, which deserves further consideration.

A high-throughput cell-based screening method for Zika virus protease inhibitor discovery

Zika virus (ZIKV) continues to pose a significant global public health threat, with recurring regional outbreaks and potential for pandemic spread. Despite often being asymptomatic, ZIKV infections can have severe consequences, including neurological disorders and congenital abnormalities. Unfortunately, there are currently no approved vaccines or antiviral drugs for the prevention or treatment of ZIKV. One promising target for drug development is the ZIKV NS2B-NS3 protease due to its crucial role in the virus life cycle. In this study, we established a cell-based ZIKV protease inhibition assay designed for high-throughput screening (HTS). Our assay relies on the ZIKV protease's ability to cleave a cyclised firefly luciferase fused to a natural cleavage sequence between NS2B and NS3 protease within living cells. We evaluated the performance of our assay in HTS setting using the pharmacologic controls (JNJ-40418677 and MK-591) and by screening a Library of Pharmacologically Active Compounds (LOPAC). The results confirmed the feasibility of our assay for compound library screening to identify potential ZIKV protease inhibitors.

Drug repurposing: identification of SARS-CoV-2 potential inhibitors by virtual screening and pharmacokinetics strategies.

The coronavirus disease 2019 (COVID-19) pandemic caused global health, economic, and population loss. Variants of the coronavirus contributed to the severity of the disease and persistent rise in infections. This study aimed to identify potential drug candidates from fifteen approved antiviral drugs against SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike protein (6M0J) using virtual screening and pharmacokinetics to gain insights into COVID-19 therapeutics. We employed drug repurposing approach to analyze binding performance of fifteen clinically approved antiviral drugs against the main protease of SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike proteins bound to ACE-2 receptor (6M0J), to provide an insight into the therapeutics of COVID-19. AutoDock Vina was used for docking studies. The binding affinities were calculated, and 2-3D structures of protein-ligand interactions were drawn. Rutin, hesperidin, and nelfinavir are clinically approved antiviral drugs with high binding affinity to proteins 6LU7, 5B6O, and 6M0J. These ligands have excellent pharmacokinetics, ensuring efficient absorption, metabolism, excretion, and digestibility. Hesperidin showed the most potent interaction with spike protein 6M0J, forming four H-bonds. Nelfinavir had a high human intestinal absorption (HIA) score of 0.93, indicating maximum absorption in the body and promising interactions with 6LU7. Our results indicated that rutin, hesperidin, and nelfinavir had the highest binding results against the proposed drug targets. The computational approach effectively identified SARS-CoV-2 inhibitors. COVID-19 is still a recurrent threat globally and predictive analysis using natural compounds might serve as a starting point for new drug development against SARS-CoV-2 and related viruses.

Pharmacokinetic Analyses of a Lipid Nanoparticle-Encapsulated mRNA-Encoded Antibody against Rift Valley Fever Virus.

Rift Valley fever virus (RVFV) could cause an emergency illness characterized by fever, muscle pain, and even death in humans or ruminants. However, there are no approved antiviral drugs that prevent or treat RVFV infection. While therapeutic antibodies have shown promising potential for prevention or treatment in several studies, many studies are ongoing, especially in the field of infectious diseases. Among these studies, the mRNA-LNP platform shows great potential for application, following the COVID-19 pandemic. Previously, we have obtained a neutralizing antibody against RVFV, which was named A38 protein and verified to have a high binding and neutralization ability. In this study, we aimed to identify an effectively optimized sequence and expressed the prioritized mRNA-encoded antibody in vitro. Notably, we effectively expressed mRNA-encoded protein and used the mRNA-LNP platform to generate A38-mRNA-LNP. Pharmacokinetic experiments were conducted in vivo and set up in two groups of mRNA-A38 group and A38 protein group, which were derived from mRNA-LNP and plasmid DNA-expressed proteins, respectively. A38-mRNA-LNPs were administrated by intramuscular injection, A38 proteins were administrated by intravenous administration, and their unique ability to maintain long-lasting protein concentrations by mRNA-encoded protein was demonstrated with the mRNA-encoded protein providing a longer circulating half-life compared to injection of the free A38 protein. These preclinical data on the mRNA-encoded antibody highlighted its potential to prevent infectious diseases in the future.

The Drug Effectiveness and Side Effects of Remdesivir in Neonatal COVID-19: A Case Series Study

: Due to the novelty of COVID-19, no definite treatment has yet been found for this infectious disease, especially in neonates and early infants. Although most of the neonates affected by this virus have a mild or silent course of the disease, in the severe form, there is no approved antiviral drug. This study was done to evaluate the safety and efficacy of Remdesivir as the known effective antiviral drug in both adults and children’s populations. In this case series study, we present our experience of the administration of Remdesivir in the treatment of 15 infants with severe neonatal COVID-19, with severe respiratory distress, admitted to our neonatal intensive care unit. We prescribed the drug with a 2 to 3-hour infusion of a loading dose of 5 mg/kg on day 1, followed by 2.5 mg/kg/day 4 days later, concomitant with continuous cardiac monitoring and blood pressure monitoring every 15 minutes. Fortunately, no side effects were reported either during or after the administration of the drug. Long-term patient follows up, for 10 months after birth, did not reveal any particular complications. It seems that the use of Remdesivir to treat severe forms of neonatal and early infancy COVID-19 is safe and effective.

Энтеровирусные неполиомиелитные инфекции у госпитализированных взрослых Краснодарского края

Objective. Characteristics of non-polio enteroviruses in outpatients in the Krasnodar. Materials and methods. The analysis of the incidence of non-polio enteroviruses in 2006–2022 was carried out in Krasnodar. The clinical course of verified non-polio enteroviruses is characterized based on the materials of a retrospective analysis of the medical stories of 157 outpatients. Results. Non-polio enteroviruses in the Krasnodar are constantly recorded in the form of sporadic morbidity with fluctuations from 0.12 to 11.26 per 100,000 population, mainly in toddlers, more often in the summer and autumn. Enterovirus meningitis prevailed in the clinical forms in the first ten years of follow-up, and in the last seven years – small forms of non-polio enteroviruses. Among adult outpatients with a moderate course of the disease predominate (98.2%), more often in the form of serous meningitis (50.9%) and exanthema of the oral mucosa and extremities (40.1%), less often acute respiratory disease (8,9%). Pathognomonic symptoms are not typical for non-polio enteroviruses. The main clinical signs of non-polio enteroviruses infection in all clinical forms are short-term febrile fever, malaise and weakness, symptoms of upper respiratory tract damage, absolute monocytosis, eosinopenia, lymphopenia, increased levels of C RP, as well as clinical and laboratory signs of serous meningitis in meningeal form and typical exanthem in "exanthem of the oral mucosa and extremities". Laboratory diagnostics should include tests to verify non-polio enteroviruses, as well as differential diagnostic studies to exclude clinically similar diseases that may involve etiotropic treatment with drugs of direct action on pathogens. The lack of approved antiviral drugs and the complexity of diagnosis lead to the inclusion of antimicrobial, broad-spectrum antiviral drugs, pathogenetic and symptomatic therapy in the treatment complex. Key words: non-polio enteroviruses, clinical characteristics, diagnosis, treatment

An Update on SARS-CoV-2 Clinical Trial Results-What We Can Learn for the Next Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has claimed over 7 million lives worldwide, providing a stark reminder of the importance of pandemic preparedness. Due to the lack of approved antiviral drugs effective against coronaviruses at the start of the pandemic, the world largely relied on repurposed efforts. Here, we summarise results from randomised controlled trials to date, as well as selected in vitro data of directly acting antivirals, host-targeting antivirals, and immunomodulatory drugs. Overall, repurposing efforts evaluating directly acting antivirals targeting other viral families were largely unsuccessful, whereas several immunomodulatory drugs led to clinical improvement in hospitalised patients with severe disease. In addition, accelerated drug discovery efforts during the pandemic progressed to multiple novel directly acting antivirals with clinical efficacy, including small molecule inhibitors and monoclonal antibodies. We argue that large-scale investment is required to prepare for future pandemics; both to develop an arsenal of broad-spectrum antivirals beyond coronaviruses and build worldwide clinical trial networks that can be rapidly utilised.

Identification of four neutralizing antigenic sites on the enterovirus D68 capsid.

Enterovirus D68 (EV-D68) is an emerging respiratory pathogen associated with acute flaccid myelitis. Currently, no approved vaccines or antiviral drugs are available. Here, we report four functionally independent neutralizing antigenic sites (I to IV) by analyses of neutralizing monoclonal antibody (MAb)-resistant mutants. Site I is located in the VP1 BC loop near the fivefold axis. Site II resides in the VP2 EF loop, and site III is situated in VP1 C-terminus; both sites are located at the south rim of the canyon. Site IV is composed of residue in VP2 βB strand and residues in the VP3 BC loop and resides around the threefold axis. The developed MAbs targeting the antigenic sites can inhibit viral binding to cells. These findings advance the understanding of the recognition of EV-D68 by neutralizing antibodies and viral evolution and immune escape and also have important implications for the development of novel EV-D68 vaccines.

The repurposing of FDA-approved drugs to stop viral replication in COVID-19 treatment: a comprehensive molecular docking and dynamics analysis

Amidst a public health crisis such as the SARS-CoV-2 induced COVID-19 pandemic, the urgency to develop and provide access to novel drugs becomes paramount. In these scenarios, repurposing existing drugs emerges as an appealing strategy due to their established safety profiles and prior regulatory approvals, potentially streamlining their adoption for new therapeutic purposes. There has been a notable interest in investigating the repurposing potential of FDA-approved drugs to combat the disease triggered by the SARS-CoV-2 virus. This investigation was conducted with the objective of identifying FDA-approved antiviral drugs that could target both the original and mutant forms of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) protein, given the escalating prevalence of SARS-CoV-2 mutations that undermined vaccine efficacy and underscored the need for alternative treatment avenues. Despite ongoing clinical trials, the selection of drugs specifically designed to combat SARS-CoV-2 remains limited. The present study aimed to assess the inhibitory potential of eight approved antiviral drugs. The wild-type and mutant (P323L) RdRp protein (PDB ID: 7BV2). By utilizing molecular docking techniques, the selected drugs were evaluated based on their binding affinities with both the mutant and wild-type RdRp protein. Subsequently, the protein-ligand complexes exhibiting the highest binding affinities were subjected to a 150 ns molecular dynamics simulation to evaluate their stability. The outcomes of the molecular docking analysis pinpointed Dolutegravir and Beclabuvir as possessing the most robust binding affinities for both mutant and wild-type RdRp systems. These findings prompted the selection of these drugs for an in-depth molecular dynamic simulation (MDS) investigation. The comprehensive analysis of Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA) and Secondary Structure Dynamics confirmed that Dolutegravir and Beclabuvir are potent inhibitors of the NSP12 protein. Collectively, the computational assessments put forth two potential contenders: Dolutegravir and Beclabuvir as promising inhibitors against both the wild-type and mutant RdRp proteins. To further validate these drug candidates, rigorous in vitro and in vivo investigations are warranted which could eventually position them as valuable therapeutic agents in the fight against COVID-19.

Inhibition of Eukaryotic Initiating Factor eIF4E Overcomes Abemaciclib Resistance in Gastric Cancer.

Aberrant activating mutations in cyclin-dependent kinases 4 and 6 (CDK4/6) are common in various cancers, including gastroesophageal malignancies. Although CDK4/6 inhibitors, such as abemaciclib and palbociclib, have been approved for breast cancer treatment, their effectiveness as a monotherapy remains limited for gastroesophageal tumors. The present study explored the underlying mechanism of abemaciclib resistance. Abemaciclib-resistant gastric cancer cell lines were generated, and the phospho-eukaryotic translation initiation factor 4E (p-eIF4E) and eIF4E expression was compared between resistant and parental cell lines. In order to analyze the role of eIF4E in cell resistance, siRNA knockdown was employed. The effectiveness of ribavirin alone and its combination with abemaciclib was evaluated in the gastric cancer xenograft mouse model. The upregulation of eIF4E was a common feature in gastric cancer cells exposed to prolonged abemaciclib treatment. Gastric cancer cells with increased eIF4E levels exhibited a better response to eIF4E inhibition, especially those that were resistant to abemaciclib. Ribavirin, which is an approved anti-viral drug, significantly improved the efficacy of abemaciclib, both in vitro and in vivo, by inhibiting eIF4E. Importantly, ribavirin effectively suppressed the abemaciclib-resistant gastric cancer growth in mice without causing toxicity. These findings suggest that targeting eIF4E can enhance the abemaciclib treatment for gastric cancer, proposing the potential combination therapy of CDK4/6 inhibitors with ribavirin for advanced gastric cancer.

Emerging Tick-Borne Dabie bandavirus: Virology, Epidemiology, and Prevention.

Severe Fever with Thrombocytopenia Syndrome (SFTS), caused by Dabie bandavirus (SFTSV), is an emerging infectious disease first identified in China. Since its discovery, infections have spread throughout East Asian countries primarily through tick bites but also via transmission between animals and humans. The expanding range of ticks, the primary vectors for SFTSV, combined with migration patterns of tick-carrying birds, sets the stage for the global spread of this virus. SFTSV rapidly evolves due to continuous mutation and reassortment; currently, no approved vaccines or antiviral drugs are available. Thus, the threat this virus poses to global health is unmistakable. This review consolidates the most recent research on SFTSV, including its molecular characteristics, transmission pathways through ticks and other animals, as well as the progress in antiviral drug and vaccine development, encompassing animal models and clinical trials.

Myricetin inhibits Micropterus salmoides rhabdovirus infection by damping inflammation through the NF-κB pathway

Largemouth bass have been plagued by diseases elicited by bacteria, parasites, and viruses, particularly viral diseases, which have caused significant economic losses in recent years. And there is a lack of approved antiviral drugs in the aquaculture industry. Micropterus salmoides Rhabdovirus (MSRV) is the causative agent of Micropterus salmoides Rhabdovirus disease, which mostly affects largemouth bass fry. By using experimental infection, transcriptome sequencing, and inhibitor treatment, the inflammatory response mediated by mitogen-activated protein kinase (MAPK), phosphatidylinositol3-kinase (PI3K), and nuclear factor kappa-B (NF-κB) pathways was verified as one of the pathological processes of MSRV infection. Further, Myricetin, arteannuin, naringenin, ursolic acid, andrographolide, and resveratrol were selected to evolute their anti-inflammatory activity based on the promoter of NF-κB and found myricetin, naringenin, andrographolide, and resveratrol significantly inhibited NF-κB 1 promoter activity. Myricetin was found to damp MSRV caused-inflammation and inhibit MSRV infection by suppressing NF-κB signaling. Besides, myricetin improves the survival rate of largemouth bass after MSRV infection. In conclusion, myricetin presented anti-MSRV activity by targeting the NF-κB inflammatory pathway and can be further developed as a potential preventative drug of rhabdovirus disease.

Knowledge, perception and safety practices of monkeypox infection among healthcare workers in a tertiary health facility in southwest Nigeria

Background: Monkeypox is a self-limiting disease first reported in 1970 in Zaire. It is characterised with small pox like eruptions and presently there is no approved anti–viral drug yet, clinical management of human monkey pox cases is mainly by supportive treatment and symptomatic treatment. This study assessed the knowledge, perception and safety practices of monkey pox disease among healthcare workers in a tertiary facility in Southwest state, Nigeria. Methods: The study was a descriptive cross-sectional study, web-based conducted among 402 healthcare workers in a tertiary health centre in Southwestern Nigeria. The 38-item survey instrument for the quantitative study was adapted from a similar study on COVID-19 among healthcare workers. Data was analysed using SPSS software version 20.0. Level of significance was pre-determined at p value <0.05 at a confidence level of 95%. Results: Female respondents constituted 241 (60%) while 161 (40%) were males. Mean age was 35.4±6.5 years with age group 26-35 years (49.0%) being the majority. Majority, 311 (77.4%) had poor knowledge of monkeypox while 69.9% had good perception. There was statistically significant association between age (α- 0.001), work experience (α- 0.001), tribe (α- 0.001), and average monthly income (α- 0.001) with perception about monkey pox infection among the respondents. Conclusions: Monkeypox is endemic in Nigeria and the knowledge and perceptions of healthcare workers towards the disease is a critical epidemiological determinant of its transmission rate, it is therefore imperative that intensive training be targeted among all cadres of healthcare professional including non-medical workers in healthcare setting.

Favipiravir and Ribavirin protect immunocompetent mice from lethal CCHFV infection

Crimean-Congo hemorrhagic fever virus (CCHFV) causes Crimean-Congo hemorrhagic fever (CCHF) in humans with high morbidity and mortality. Currently, there is neither an approved antiviral drug nor a vaccine against CCHFV. In this study, we describe a lethal model of CCHFV infection using a mouse-adapted strain of CCHFV (MA-CCHFV) in adult wild-type male mice. Infected mice developed high viral loads, tissue pathology, and inflammatory immune responses before ultimately succumbing to the infection. We used the model to evaluate the protective efficacy of nucleoside analogs monulpiravir, favipiravir, ribavirin, the antibiotic tigecycline and the corticosteroids dexamethasone and methylprednisolone against lethal CCHFV infection. Tigecycline, monulpiravir and the corticosteroids failed to protect mice from lethal MA-CCHFV infection. In contrast, favipiravir and ribavirin protected animals from clinical disease and death even when treatment was delayed. Despite demonstrating uniform protection, CCHFV RNA persisted in survivors treated with favipiravir and ribavirin. Nevertheless, the study demonstrated the anti-CCHFV efficacy of favipiravir and ribavirin in a model with intact innate immunity and establishes this model for continued development of CCHFV countermeasures.

Mangiferin and Taurine Ameliorate MSRV Infection by Suppressing NF-κB Signaling.

The emergence or reemergence of viruses pose a substantial threat and challenge to the world population, livestock, and wildlife. However, the landscape of antiviral agents either for human or animal viral diseases is still underdeveloped. The far tougher actuality is the case that there are no approved antiviral drugs in the aquaculture industry, although there are diverse viral pathogens. In this study, using a novel epithelial cell line derived from the brain of Micropterus salmoides (MSBr), inflammation and oxidative stress were found to implicate the major pathophysiology of M. salmoides rhabdovirus (MSRV) through transcriptome analysis and biochemical tests. Elevated levels of proinflammatory cytokines (interleukin-1β [IL-1β], IL-6, IL-8, tumor necrosis factor alpha [TNF-α], and gamma interferon [IFN-γ]) and accumulated contents of reactive oxygen species (ROS) as well as biomarkers of oxidative damage (protein carbonyl and 8-OHdG) were observed after MSRV infection in the MSBr cells. Mangiferin or taurine dampened MSRV-induced inflammation and rescued the oxidative stress and, thus, inhibited the replication of MSRV in the MSBr cells with 50% effective concentration (EC50) values of 6.77 μg/mL and 8.02 μg/mL, respectively. Further, mangiferin or taurine hampered the activation of NF-κB1 and the NF-κB1 promoter as well as the increase of phosphorylated NF-κB (p65) protein level induced by MSRV infection, indicating their antiviral mechanism by suppressing NF-κB signaling. These findings exemplify a practice approach, aiming to dampen and redirect inflammatory responses, to develop broad-spectrum antivirals. IMPORTANCE Aquaculture now provides almost half of all fish for human food in 2021 and plays a significant role in eliminating hunger, promoting health, and reducing poverty. There are diverse viral pathogens that decrease production in aquaculture. We developed a novel epithelial cell line derived from the brain of Micropterus salmoides, which can be used for virus isolation, gene expressing, and drug screening. In this study, we focus on M. salmoides rhabdovirus (MSRV) and revealed its pathophysiology of inflammation and oxidative stress. Aiming to dampen and redirect inflammatory responses, mangiferin or taurine exhibited their antiviral capability by suppressing NF-κB signaling. Our findings exemplify a practice approach to develop broad-spectrum antivirals by dampening and redirecting inflammatory responses.

Vemurafenib Inhibits Acute and Chronic Enterovirus Infection by Affecting Cellular Kinase Phosphatidylinositol 4-Kinase Type IIIβ.

Enteroviruses are one of the most abundant viruses causing mild to serious acute infections in humans and also contributing to chronic diseases like type 1 diabetes. Presently, there are no approved antiviral drugs against enteroviruses. Here, we studied the potency of vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAFV600E mutant-related melanoma, as an antiviral against enteroviruses. We showed that vemurafenib prevented enterovirus translation and replication at low micromolar dosage in an RAF/MEK/ERK-independent manner. Vemurafenib was effective against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect was related to a cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevented infection efficiently in acute cell models, eradicated infection in a chronic cell model, and lowered virus amounts in pancreas and heart in an acute mouse model. Altogether, instead of acting through the RAF/MEK/ERK pathway, vemurafenib affects the cellular PI4KB and, hence, enterovirus replication, opening new possibilities to evaluate further the potential of vemurafenib as a repurposed drug in clinical care. IMPORTANCE Despite the prevalence and medical threat of enteroviruses, presently, there are no antivirals against them. Here, we show that vemurafenib, an FDA-approved RAF kinase inhibitor for treating BRAFV600E mutant-related melanoma, prevents enterovirus translation and replication. Vemurafenib shows efficacy against group A, B, and C enteroviruses, as well as rhinovirus, but not parechovirus or more remote viruses such as Semliki Forest virus, adenovirus, and respiratory syncytial virus. The inhibitory effect acts through cellular phosphatidylinositol 4-kinase type IIIβ (PI4KB), which has been shown to be important in the formation of enteroviral replication organelles. Vemurafenib prevents infection efficiently in acute cell models, eradicates infection in a chronic cell model, and lowers virus amounts in pancreas and heart in an acute mouse model. Our findings open new possibilities to develop drugs against enteroviruses and give hope for repurposing vemurafenib as an antiviral drug against enteroviruses.