Antiviral Research Articles

Exploring Antiviral Drugs on Monolayer Black Phosphorene: Atomistic Theory and Explainable Machine Learning-Assisted Platform.

Favipiravir (FP) and ebselen (EB) belong to a diverse class of antiviral drugs known for their significant efficacy in treating various viral infections. Utilizing molecular dynamics (MD) simulations, machine learning, and van der Waals density functional theory, we accurately elucidate the binding properties of these antiviral drugs on a phosphorene single-layer. To further investigate these characteristics, this study employs four distinct machine learning models-Random Forest, Gradient Boosting, XGBoost, and CatBoost. The Hamiltonian of antiviral molecules within a monolayer of phosphorene is appropriately trained. The key aspect of utilizing machine learning (ML) in drug design revolves around training models that are efficient and precise in approximating density functional theory (DFT). Furthermore, the study employs SHAP (SHapley Additive exPlanations) to elucidate model predictions, providing insights into the contribution of each feature. To explore the interaction characteristics and thermodynamic properties of the hybrid drug, we employ molecular dynamics and DFT calculations in a vacuum interface. Our findings suggest that this functionalized 2D complex exhibits robust thermostability, indicating its potential as an effective and enabled entity. The observed variations in free energy at different surface charges and temperatures suggest the adsorption potential of FP and EB molecules from the surrounding environment.

Sustained release delivery of favipiravir through statistically optimized, chemically cross-linked, pH-sensitive, swellable hydrogel.

In the current work, favipiravir (an antiviral drug) loaded pH-responsive polymeric hydrogels were developed by the free redical polymerization technique. Box-Behnken design method via Design Expert version 11 was employed to furnish the composition of all hydrogel formulations. Here, polyethylene glycol (PEG) has been utilized as a polymer, acrylic acid (AA) as a monomer, and potassium persulfate (KPS) and methylene-bisacrylamide (MBA) as initiator and cross-linker, respectively. All networks were evaluated for in-vitro drug release (%), sol-gel fraction (%), swelling studies (%), porosity (%), percentage entrapment efficiency, and chemical compatibilities. According to findings, the swelling was pH sensitive and was shown to be greatest at a pH of 6.8 (2500%). The optimum gel fraction offered was 97.8%. A sufficient porosity allows the hydrogel to load a substantial amount of favipiravir despite its hydrophobic behavior. Hydrogels exhibited maximum entrapment efficiency of favipiravir upto 98%. The in-vitro release studies of drug-formulated hydrogel revealed that the drug release from hydrogel was between 85 to 110% within 24 h. Drug-release kinetic results showed that the Korsmeyer Peppas model was followed by most of the developed formulations based on the R2 value. In conclusion, the hydrogel-based technology proved to be an excellent option for creating the sustained-release dosage form of the antiviral drug favipiravir.

Synthesis of Gem-Dimethyl Bicyclic [3.1.0] Proline as an Antiviral Drug Intermediate

Abstract: Gem-dimethyl bicyclic [3.1.0] proline, an azadicyclohexane derivative, constitutes a prevalent skeleton structure in drugs, which serves an important role in the synthesis of antiviral drugs, such as Nirmatrelvir, Boceprevir, Narlaprevir, etc. This study offers a comprehensive overview of the documented synthetic strategies for gem-dimethyl bicyclic [3.1.0] proline methyl ester and delves into the application characteristics of each synthetic strategy. These synthetic approaches can be divided into three major types: the first synthetic method uses proline derivatives as the starting material, the second one uses cyclopropane derivatives as the starting material, and the third one uses the bicyclic skeleton as the starting material. Of these strategies, the third method stands out as the most extensively adopted.

Quality by Design-driven Analytical Method: A Quality Risk Management-Based Liquid Chromatography Method for Daclatasvir and Characterization of its Putative Degradants by LC-MS/MS

Background:: Antiviral drugs can cure more than 95 percent of people with hepatitis C, but the inaccessibility of quality affordable medicines and the lack of their uninterrupted supply pose a major challenge. Impurities in drugs have a significant impact on their quality and are one of the substantial causes of drug recalls, ultimately leading to the unavailability of the drug in the market. Hence, there is a need for a robust, quality risk management and quality by design-driven analytical method that can detect the antiviral drug, Daclatasvir dihydrochloride, in the presence of its probable impurities. Objective:: This study aimed to develop a Quality by Design-driven stability- indicating liquid chromatography method for Daclatasvir dihydrochloride and the characterization of its putative degradants by LC-MS. Method:: The fishbone diagram and quality risk assessment investigated twenty-four process parameters and concluded that three risk parameters, i.e., flow rate, buffer pH, and stationary phase type, were the critical process parameters. The critical quality attributes viz. resolution between impurity 6 and DCV and impurity 2 & 3 (Rs˃1.5), the shape of the peak of DCV which is decided by the Number of Theoretical Plates (NTP˃5000), and the retention time of Daclatasvir (tR14-23 mins) were optimized using a two-level three-factor full factorial design with five center points. Results:: The optimized method is stability-indicating in its true sense as it can separate the sample with its degradants generated in basic (three), acidic (two), oxidative (H2O2: three, Azobisisobutyronitrile: one), photo (three), and dry heat (one) conditions. Degradants structures were elucidated, and degradation routes were established, using LC-MS and LC-MS/MS analyses. Conclusion:: The drug is highly susceptible to acid, base hydrolysis, and oxidation degradation conditions and poses a significant risk to the analytical method to fail in system suitability criteria. Hence, a robust and flexible chromatographic method with the capacity for continuous improvement was developed and successfully validated within the criteria of design space.

Anti-HSV activity of nectin-1-derived peptides targeting HSV gD: an in-silico and in-vitro approach

Herpes simplex virus (HSV) infections affect a wide range of the global population. The emergence of resistance to the existing anti-HSV therapy highlights the necessity for an innovative strategy. The interaction of HSV gD with its main host receptor nectin-1 is a potential target for new antiviral drugs. The aim of this study was to develop a peptide derived from nectin-1 targeting HSV gD using the in-silico method and evaluate them for anti-HSV activity. Residues 59-133 of the Nectin-1 V-domain constitute the interaction interface with HSV gD. Bioinformatic tools viz., PEP-FOLD3, ClusPro 2.0, HawkDock and Desmond were used to model the peptide and confirm its binding specificity with HSV gD protein. The peptides with potential interactions were custom synthesized and anti-HSV activity was evaluated in vitro against HSV-1 and HSV-2 by CPE inhibition assay. Five peptide sequences were identified as exhibiting good interaction with HSV-gD proteins. Among them, peptide N1 (residues 76–90) offered maximum protection against HSV-1 (66.57%) and HSV-2 (71.12%) infections. Modification of the identified peptide through peptidomimetic approaches may further enhance the activity and stability of the identified peptide. Communicated by Ramaswamy H. Sarma

Chemical compounds investigation and profiling of antimicrobial and antiviral constituents of <i>Tephrosia purpurea</i> subsp. <i>apollinea</i>

Tephrosia purpurea subsp. apollinea belongs to the family Fabaceae, and it is distributed in the delta region of Egypt. It has been used in traditional medicine for the management of various diseases. This study aimed to identify the phytochemicals utilizing LC/MS, and biological properties of a methanolic extract of Tephrosia purpurea subsp. apollinea. The analysis identified 31 compounds representing various phytochemical classes, including fatty acids, sterols, phenolic acids, polyphenols, terpenoids, and flavonoids. Among the major compounds detected, linoleic acid (13.2%) and campesterol (10.1%) were the most abundant. The extract displayed antibacterial, antifungal, and antiviral activities. The methanolic extract demonstrated varying degrees of antimicrobial activity against the tested microorganisms, with Bacillus subtilis showing the highest susceptibility. Significant antiviral activity was observed against herpes simplex and hepatitis C viruses. These findings highlight the potential of T. purpurea subsp. apollinea as a valuable source of natural bioactive compounds including antiviral agents. Additional investigation is required to explore the active principles responsible for the observed biological properties and their therapeutic applications in combating bacterial, fungal, and viral infections.

The Role of Tecovirimat in the Management of Monkeypox

Monkeypox is a self-limited disease with symptoms that disappear within 14 to 21 days. Clinical management of monkeypox includes general supportive care and the use of antivirals that have activity against the monkeypox virus. This literature study aims to describe the role of tecovirimat in the management of monkeypox. Tecovirimat is an antiviral drug approved by the U.S. Food and Drug Administration (FDA) as part of the treatment management of smallpox in adults and children. Evidence of the efficacy of tecovirimat as mpox therapy was obtained from animal studies, where tecovirimat reduced mortality rates, reduced duration of illness and viral shedding. Tecovirimat inhibits the vp37 viral protein encoded by the F13 gene of the variola virus. This protein is highly conserved in orthopoxviruses, allowing tecovirimat to have in vitro activity against several orthopoxviruses, including vaccinia, variola, cowpox, and monkeypox viruses. In conclusion, tecovirimat is used in monkeypox sufferers with severe clinical conditions (sepsis, encephalitis, extensive lesions, bleeding manifestations), patients at risk of experiencing severe clinical conditions (immunocompromised, pregnant or breastfeeding, history of psoriasis, varicella zoster infection) and patients with one or more complications.

HCV drug resistance mutations in HIV-infected patients

The aim of our work was to assess prevalence in the HCV drug resistance mutations in the NS3, NS5A, NS5B genes in HIV-infected patients. The material of the study was 157 blood plasma samples collected from HIV patients living in the Leningrad Region, with virological inefficiency of antiretroviral therapy. Samples were examined for the presence of anti-HCV antibodies and HCV RNA using commercial test systems in accordance with the manufacturer’s recommendations. In the case of detecting HCV RNA, amplification reaction was carried out using a set of primers co-flanking the NS3, NS5A, and NS5B genes. After sequencing the nucleotide sequences of the above genes, the virus subtype was determined. To assess HCV drug resistance mutations to direct-acting antiviral agents (DAAs), the Geno2pheno HCV resistance software (https:// hcv.geno2pheno.org) was used. The age of the patients varied from 18 to 65 and averaged 34.3±7.27 years. The number of males vs females prevailed comprising 71% and 28%, respectively. Antibodies against HCV were detected in 94.2% cases, whereas HCV RNA — in 98 (61.7%) HIV-infected persons. The distribution of HCV genotypes in this group was as follows: 1a — 7% (n = 7), 1b — 53% (n = 52), 2 — 2% (n = 2), 3a — 38% (n = 37). The results of determining the viral load varied from 5.3 × 103 to 2.3 × 108 IU/ml. The nucleotide sequence of all three regions NS3, NS5A, NS5B was determined in 73 samples. Analysis of drug resistance mutations in the NS3 region was performed for 82 HCV isolates of genotypes 1b (n = 46), 3a (n = 31), 1a (n = 4), 2 (n = 1). In total, the proportion of strains containing mutations in the NS3 region was 9.8%. The presence of significant amino acid substitutions in the NS5A region was tested for 83 HCV isolates of genotypes 1b (n = 47), 3a (n = 30), 1a (n = 6). The percentage of strains containing mutations in the NS5A region was 19.3%. Resistance mutations in the NS5B region were analysed for 87 HCV isolates of genotypes 1b (n = 48), 3a (n = 32), 2 (n = 2), 1a (n = 5). The proportion of strains containing mutations in the NS5B region was 11.5%. In the study group, mutations associated with hepatitis C virus resistance to DAAs in all regions were found in 16.6% (95% CI: 11.11–23.32%) cases (n = 26). In the NS3, NS5A and NS5B, there have been identified 6, 15 and 10 significant amino acid substitutions, respectively.

Antiviral Activity of Low-Molecular-Weight Fluorinated Compounds Against Influenza A (H1N1) Virus

Influenza A virus takes a stable position in annual acute respiratory disease outbreaks during the autumn-winter period. Antiviral drugs for influenza infection help significantly ease the course of the disease and prevent complications, but there is still no drug to which none of the circulating strains would be resistant. Therefore, the search for new effective drugs against influenza A virus is constantly being conducted, in particular among fluorine-containing organic compounds, taking into account the special properties of fluorine. The goal of the study is to investigate the activity of a group of low-molecular-weight fluorinated compounds against the influenza A (H1N1) virus and to determine the potential mechanism of their action using in silico methods. Methods. Five fluorinated compounds designated as 10S-45, 10S-46, 10S-47, 10S-48 and 10S-49 were studied. In vitro experiments were performed using MDCK cell culture, A/FM/1/47 strain of influenza A (H1N1) virus, and oseltamivir phosphate as a reference drug. The cytotoxic effect on cell culture was determined using the MTT test. Antiviral effect was investigated by post-exposure incubation of compound solutions with cells, and visualization of results was performed using crystal violet dye. The possibility of the interaction of compounds with the cap-binding domain (CBD) of the PB2 subunit of the RNA-dependent RNA polymerase (RdRp) of the virus was evaluated using molecular dynamics simulation. Results. It was established that the studied compounds have a moderate cytotoxic effect on MDCK cell culture: the calculated CC50 values are in the range of 471─577 μg/mL for 10S-45, 10S-46, 10S-47 and 10S-48. Substance 10S-49 is almost 2 times less toxic compared to the rest, but it also has no effect on the influenza virus. Compounds 10S-45, 10S-46 and 10S-48 demonstrate antiviral activity in the range of 12─78 % inhibition of viral reproduction with an inverse dose-dependent effect. Substance 10S-47 showed a relatively stable inhibition of viral reproduction in the range of 63─69 % at all tested concentrations, which is similar to the results of the reference drug. According to the results of the selectivity index calculation, compound 10S-48 has the highest value, and 10S-47 has the lowest one, for the rest of the substances, this indicator is acceptable, but low, compared to the reference drug. For in silico studies, all possible spatial forms of the compounds presented as a mixture of diastereoisomers were generated: 4 stereoisomers each for 10S-45 and 10S-46, as well as 3 for 10S-47. According to the results of molecular docking of substances to the active center of CBD, 10S-45 has the lowest calculated affinity, and 10S-47 has the highest. Accordingly, compound 10S-45 showed no tendency to form ordered interactions with CBD. The 10S-47/CBD complex was not characterized by the presence of stable orientational bonds between receptor and ligand, similar to 10S-48/CBD. However, compound 10S-46 showed a generally stable interaction with CBD, albeit with a period of conformational instability. Conclusions. All studied compounds (except for 10S-49) demonstrate an antiviral effect in vitro against the influenza A (H1N1) virus. Based on the results of the in silico analysis of their interactions with CBD PB2, compound 10S-46 is highly likely to be an inhibitor of the cap-binding activity of RdRp.

Anti-viral Effects of Pavetta indica Methanolic Extract and Acyclovir on Behavioral and Biochemical Parameters in Streptozotocin-induced Alzheimer's Disease in Rats.

Alzheimer's disease is a neurological dysfunction of the brain caused by neurodegeneration and oxidative stress. Some viruses, such as herpes viruses, HSV-1, and HSV-2, are causative agents of Alzheimer's disease and result in β-amyloid peptide and tau protein accumulation in the brain. Some antiviral drugs, such as valacyclovir, acyclovir, and foscarnet, reduce amyloid-beta and P-tau. Pavetta indica leaves are also reported for their antiviral properties. The current study aimed to find out the significance of using Pavetta indica methanolic extract and acyclovir against Alzheimer's disease induced by streptozotocin. Wistar rats received acyclovir and Pavetta indica methanolic extract orally at different dose ranges (50, 150, 450 mg/kg) and (125, 250, 500 mg/kg), respectively. The standard therapy, Rivastigmine (2 mg/kg), was given orally. Intracerebroventricular-streptozotocin produced significant alternations in behavioral assessments, including locomotor activity test, Morris water maze test, and elevated plus maze test. Moreover, intracerebroventricular-streptozotocin ameliorated the antioxidant defense activity by decreasing levels of catalase, superoxide dismutase, and reduced glutathione while enhancing the oxidative stress markers, including malondialdehyde, and total nitrite levels. Finally, the main findings showed that intracerebroventricular-streptozotocin significantly increased the inflammatory marker, tumor necrosis factor-α, and disturbed neurotransmitter mediators, including levels of acetylcholinesterase, glutamate, and γ-amino butyric acid. In a dose-dependent manner, acyclovir and Pavetta indica methanolic extract treatments abrogated the streptozotocin-induced behavioral and neurological abnormalities in rats. The potential therapeutic effects of PIME and acyclovir administration in intracerebroventricular-streptozotocin-treated rats may be attributed to its potential antiviral, antioxidant, and anti-inflammatory effects. The current study suggests that Pavetta indica methanolic extract and acyclovir are promising therapeutic targets against Alzheimer's disease.

Challenges in Treating Pediatric Cancer Patients during the COVID-19 Pandemic: Balancing Risks and Care

The COVID-19 pandemic has resulted in millions of fatalities worldwide. The case of pediatric cancer patients stands out since, despite being considered a population at risk, few studies have been carried out concerning symptom detection or the description of the mechanisms capable of modifying the course of the COVID-19 disease, such as the interaction and response between the virus and the treatment given to cancer patients. By synthesizing existing studies, this paper aims to expose the treatment challenges for pediatric patients with COVID-19 in an oncology context. Additionally, this updated review includes studies that utilized the antiviral agents Remdesivir and PaxlovidTM in pediatric cancer patients. There is no specific treatment designed exclusively for pediatric cancer patients dealing with COVID-19, and it is advisable to avoid self-medication to prevent potential side effects. Managing COVID-19 in pediatric cancer patients is indeed a substantial challenge. New strategies, such as chemotherapy application rooms, have been implemented for children with cancer who were positive for COVID-19 but asymptomatic since the risk of disease progression is greater than the risk of complications from SARS-CoV-2.

Structural basis of Zika virus NS1 multimerization and human antibody recognition

Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family along with the four serotypes of dengue virus (DENV1–4). The recent global outbreaks of contemporary ZIKV strains demonstrated that infection can lead to neurological sequelae in adults and severe abnormalities in newborns that were previously unreported with ancestral strains. As such, there remains an unmet need for efficacious vaccines and antiviral agents against ZIKV. The non-structural protein 1 (NS1) is secreted from the infected cell and is thought to be associated with disease severity besides its proven usefulness for differential diagnoses. However, its physiologically relevant structure and pathogenesis mechanisms remain unclear. Here, we present high-resolution cryoEM structures of ZIKV recombinant secreted NS1 (rsNS1) and its complexes with three human monoclonal antibodies (AA12, EB9, GB5), as well as evidence for ZIKV infection-derived secreted NS1 (isNS1) binding to High Density Lipoprotein (HDL). We show that ZIKV rsNS1 forms tetramers and filamentous repeats of tetramers. We also observed that antibody binding did not disrupt the ZIKV NS1 tetramers as they bound to the wing and connector subdomain of the β-ladder. Our study reveals new insights into NS1 multimerization, highlights the need to distinguish the polymorphic nature of rsNS1 and isNS1, and expands the mechanistic basis of the protection conferred by antibodies targeting NS1.

Long COVID: Epidemiology, post-COVID-19 manifestations, possible mechanisms, treatment, and prevention strategies – A review

Background and objectives: The respiratory disease COVID-19 began in 2019 and quickly became a pandemic infecting millions of individuals across the globe. Many patients show lingering effects of the infection several days after testing negative for the disease. This has become known as “long COVID” and is defined by various sources as lasting anywhere from 4 weeks to periods. This is a review of the existing literature on long COVID which offersextensive insights into its clinical features, diagnosis, and treatment. Materials and method: Information on clinical features, mechanisms, treatment options, preventive measures, and epidemiology of long COVID is derived from an extensive review of scientific journals and pertinent authoritative sources. Results: The virus enters the cells via angiotensin-converting enzyme 2(ACE2) receptors. ACE2 receptors are present on numerous cell types throughout the body and thus the virus can affect several organs resulting in avariety of different symptoms. Long COVID symptoms include fatigue, dyspnea, headache, brain fog, and symptoms related to cardiovascular and pulmonary systems. Fatigue can affect upwards of 93% of patients suffering from long COVID. Failure of the body to clear the virus could initiate this chronic effect. Studies indicate that the use of antiviral drugs at the early phase of COVID-19 could prevent long COVID symptoms. Vaccines against SARS-CoV-2 also might help prevent long COVID. Conclusion: Diagnosing and managing long COVID is challenging due to diverse symptoms, including mental health issues like anxiety and depression. Longitudinal studies and patient-oriented approaches are crucial for treatment, supported by policies and educational campaigns. Understanding the pathophysiology remains a top priority. July 2024; Vol. 18(2):003. DOI: https://doi.org/10.55010/imcjms.18.015 *Correspondence: M. S. Zaman, Department of Biological Sciences, Alcorn State University, Lorman, MS 39096, USA; Department of Biology, South Texas College, McAllen, TX 78501, USA. Emails: zaman@alcorn.edu; mzaman@southtexascollege.edu

Caboxamycin Inhibits Heart Inflammation in a Coxsackievirus B3-Induced Myocarditis Mouse Model

Coxsackievirus B3 (CVB3) is a positive single-strand RNA genome virus which belongs to the enterovirus genus in the picornavirus family, like poliovirus. It is one of the most prevalent pathogens that cause myocarditis and pancreatitis in humans. However, a suitable therapeutic medication and vaccination have yet to be discovered. Caboxamycin, a benzoxazole antibiotic isolated from the culture broth of the marine strain Streptomyces sp., SC0774, showed an antiviral effect in CVB3-infected HeLa cells and a CVB3-induced myocarditis mouse model. Caboxamycin substantially decreased CVB3 VP1 production and cleavage of translation factor eIF4G1 from CVB3 infection. Virus-positive and -negative strand RNA was dramatically reduced by caboxamycin treatment. In addition, the cleavage of the pro-apoptotic molecules BAD, BAX, and caspase3 was significantly inhibited by caboxamycin treatment. In animal experiments, the survival rate of mice was improved following caboxamycin treatment. Moreover, caboxamycin treatment significantly decreased myocardial damage and inflammatory cell infiltration. Our study showed that caboxamycin dramatically suppressed cardiac inflammation and mouse death. This result suggests that caboxamycin may be suitable as a potential antiviral drug for CVB3.

In Vitro Anti-Rotaviral Activity of Bavachin Isolated from Psoralea corylifolia L. (Fabaceae)

Rotavirus is the main causative agent of viral gastroenteritis among young animals worldwide. Currently, no clinically approved or effective antiviral drugs are available to combat rotavirus infections. Herein, we evaluated the anti-rotaviral activities of extracts and bavachin isolated from Psoralea corylifolia L. (Fabaceae) (P. corylifolia) against the bovine rotavirus G8P[7] and porcine rotavirus G5P[7] in vitro. Two assay strategies were performed: (1) a virucidal assay to reduce viral infectivity by virus neutralization and (2) a post-treatment assay to assess viral replication suppression. The results from the virucidal assay showed that the extracts and bavachin did not exert anti-rotaviral activities. In the follow-up analysis after treatment, bavachin exhibited robust antiviral efficacy, with 50% effective concentration (EC50) values of 10.6 μM (selectivity index [SI] = 2.38) against bovine rotavirus G8P[7] and 13.0 μM (SI = 1.94) against porcine rotavirus G5P[7]. Bavachin strongly suppressed viral RNA synthesis in the early (6 h) and late stages (18 h) after rotaviral infection. These findings strongly suggest that bavachin may have hindered the virions by effectively inhibiting the early stages of the virus replication cycle after rotaviral infection. Furthermore, confocal imaging showed that bavachin suppressed viral protein synthesis, notably that of the rotaviral protein (VP6). These results suggest that bavachin has strong antiviral activity against rotaviruses, inhibits viral replication, and is a candidate natural therapeutic drug targeting rotaviral infection. The utilization of bavachin isolated from P. corylifolia may contribute to decreased mortality rates, lower medication expenses, and enhanced economic viability in domestic farms.

Cheminformatics and QSAR‐Based Identification of Natural Bioactive Compounds as Potent Inhibitors of SARS‐CoV‐2 N‐7 Methyltransferases

AbstractEver since the emergence of the COVID‐19 pandemic, to date, no specific and efficient therapeutic cure is available for the SARS‐CoV‐2 viral infection. Few reports have been observed with the late cardiovascular or neurodegenerative disorders that are associated with altered immunity. The nsp14 protein of SARS‐CoV‐2 is a key target for antiviral drug development as it controls replication of virus and evasion of host immune system. In this study, a consensus of cheminformatics approaches involving virtual screening, molecular docking, ADMET profiling, molecular dynamics simulations, free‐energy landscape, MM‐GBSA, DFT and 2D‐QSAR analysis is employed to discover the inhibitor of nsp14 protein. Our investigation reveals four natural bioactive compounds, i. e. ZINC2132169, ZINC8791872, ZINC8952607 and ZINC6624334 that possess enhanced binding affinity towards nsp14 protein with no predicted toxicity. Molecular docking, MD simulations and MM‐GBSA analysis established that all hit compounds strongly bind at the same pocket through hydrophobic interactions and hydrogen bonding. DFT analysis revealed greater reactivity of hit compounds and their stable complex formation with nsp14 protein, while the 2D‐QSAR (R2=0.92) predicted their pIC50 value in the range of 5.30–6.71 nM. These findings imply that hit compounds would be potent drug candidates in controlling the SARS‐CoV‐2 by inhibiting nsp14 protein.

Nanoparticles‐based double‐stranded RNA delivery as an antiviral agent in shrimp aquaculture

AbstractThe review encapsulates the comprehensive exploration of RNA interference technology's application in shrimp aquaculture, covering molecular intricacies, production methods, and practical applications. The emphasis is on exploring the stability and delivery of gene‐specific double‐stranded RNA, particularly through nanoencapsulation. This is because the susceptibility of dsRNA to degradation and limited cellular penetration, emphasising the need for effective delivery mechanisms. The review presents an in‐depth exploration of nanoparticles for the encapsulation and delivery of dsRNA, including virus‐like particles (VLPs), and non‐viral based nanoparticles such as liposomes, chitosan, and beta‐glucan. VLPs, derived from non‐infectious shrimp virus structures, exhibit biocompatibility and natural functionality, making them suitable carriers for dsRNA. The application of chitosan and its derivatives are explored for their efficacy in reducing viral infections in shrimp. Beta‐glucan particles are examined for their immunostimulant properties in shrimp aquaculture. The text emphasises the use of yeast‐based glucan particles for encapsulating dsRNA, showcasing their potential in preventing viral diseases in shrimp. The review introduces cautionary considerations for nanoparticle formulation, highlighting factors such as pH, organic solvents, metal ions, and environmental ribonuclease that can impact dsRNA stability during synthesis. In conclusion, the text discusses the potential economic worthiness and environmental risk assessment of dsRNA technology in shrimp aquaculture. While acknowledging successful applications in other environments, it underscores the need for regulatory approval and risk assessment for dsRNA‐based products in the aquaculture industry. The evaluation of dsRNA in real‐world shrimp farms is deemed necessary for commercial utilisation, taking into account income, expenses, safety, and environmental considerations.

Oxymatrine Modulation of TLR3 Signaling: A Dual-Action Mechanism for H9N2 Avian Influenza Virus Defense and Immune Regulation.

In our research, we explored a natural substance called Oxymatrine, found in a traditional Chinese medicinal plant, to fight against a common bird flu virus known as H9N2. This virus not only affects birds but can also pose a threat to human health. We focused on how this natural compound can help in stopping the virus from spreading in cells that line the lungs of birds and potentially humans. Our findings show that Oxymatrine can both directly block the virus and boost the body's immune response against it. This dual-action mechanism is particularly interesting because it indicates that Oxymatrine might be a useful tool in developing new ways to prevent and treat this type of bird flu. Understanding how Oxymatrine works against the H9N2 virus could lead to safer and more natural ways to combat viral infections in animals and humans, contributing to the health and well-being of society. The H9N2 Avian Influenza Virus (AIV) is a persistent health threat because of its rapid mutation rate and the limited efficacy of vaccines, underscoring the urgent need for innovative therapies. This study investigated the H9N2 AIV antiviral properties of Oxymatrine (OMT), a compound derived from traditional Chinese medicine, particularly focusing on its interaction with pulmonary microvascular endothelial cells (PMVECs). Employing an array of in vitro assays, including 50% tissue culture infectious dose, Cell Counting Kit-8, reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot, we systematically elucidated the multifaceted effects of OMT. OMT dose-dependently inhibited critical antiviral proteins (PKR and Mx1) and modulated the expression of type I interferons and key cytokines (IFN-α, IFN-β, IL-6, and TNF-α), thereby affecting TLR3 signaling and its downstream elements (NF-κB and IRF-3). OMT's antiviral efficacy extended beyond TLR3-mediated responses, suggesting its potential as a versatile antiviral agent. This study not only contributes to the growing body of research on the use of natural compounds as antiviral agents but also underscores the importance of further investigating the broader application of OMT for combating viral infections.

Biophysical and structural study of La Crosse virus endonuclease inhibition for the development of new antiviral options.

The large Bunyavirales order includes several families of viruses with a segmented ambisense (-) RNA genome and a cytoplasmic life cycle that starts by synthesizing viral mRNA. The initiation of transcription, which is common to all members, relies on an endonuclease activity that is responsible for cap-snatching. In La Crosse virus, an orthobunyavirus, it has previously been shown that the cap-snatching endonuclease resides in the N-terminal domain of the L protein. Orthobunyaviruses are transmitted by arthropods and cause diseases in cattle. However, California encephalitis virus, La Crosse virus and Jamestown Canyon virus are North American species that can cause encephalitis in humans. No vaccines or antiviral drugs are available. In this study, three known Influenza virus endonuclease inhibitors (DPBA, L-742,001 and baloxavir) were repurposed on the La Crosse virus endonuclease. Their inhibition was evaluated by fluorescence resonance energy transfer and their mode of binding was then assessed by differential scanning fluorimetry and microscale thermophoresis. Finally, two crystallographic structures were obtained in complex with L-742,001 and baloxavir, providing access to the structural determinants of inhibition and offering key information for the further development of Bunyavirales endonuclease inhibitors.

Adherence in HCV Treatment: What We Know.

Although therapy with direct-acting antiviral (DAA) agents achieves high HCV cure rates and is forgiving of missed doses, certain patient populations, such as people who inject drugs (PWID), are often denied therapy because of a perceived high risk of nonadherence. However, a relationship between adherence to DAAs for various patient populations and efficacy has not been well defined. The lack of a standardized method for evaluating adherence complicates making comparisons between studies, making it difficult to develop and implement novel measures that may improve adherent behavior. Traditional methods for assessing adherence may overestimate medication adherence, while newer, technology-based methods may assist with accurately assessing and maintaining patient adherence to therapy. Data demonstrate that special populations of patients with HCV, such as PWID, can be successfully treated, with relatively high rates of sustained virologic response (SVR) despite less-than-optimal adherence. While rates of adherence, and subsequently SVR, can be improved, antiviral therapy should not be withheld because of fear of nonadherence. This paper addresses medication adherence and forgiveness of DAA regimens, such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, in different patient populations with HCV. Considerations in evaluating adherence in HCV therapy and available methods for assessing adherence are detailed.