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Zika virus (ZIKV; family, Flaviviridae), which causes congenital Zika syndrome, Guillain-Barré Syndrome, and other severe diseases, is transmitted mainly by mosquitoes; however, the virus can be transmitted through other routes. Among the three structural and seven nonstructural proteins, the surface envelope (E) protein of ZIKV plays a critical role in viral entry and pathogenesis, making it a key target for the development of effective entry inhibitors. This review article describes the life cycle, genome, and encoded proteins of ZIKV, illustrates the structure and function of the ZIKV E protein, summarizes E protein-targeting entry inhibitors (with a focus on those based on natural products and small molecules), and highlights challenges that may potentially hinder the development of effective inhibitors of ZIKV infection. Overall, the article will provide useful guidance for further development of safe and potent ZIKV entry inhibitors targeting the viral E protein.

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Eczema herpeticum (EH) is a severe viral complication caused by the herpes simplex virus (HSV) that occurs in individuals with compromised skin barriers, such as those with atopic dermatitis (AD). EH is characterized by the rapid spread of HSV across skin lesions, potentially leading to systemic involvement. Although commonly observed in the context of AD, EH can also arise in various dermatological conditions, necessitating prompt recognition and management by healthcare providers. This case report details the diagnosis and treatment of EH in a five-year-old girl with a history of AD who presents with fever and painful skin lesions. Despite the absence of confirmatory tests initially, a positive IgM anti-HSV-1 serology, combined with clinical presentation, supported the diagnosis of EH. The patient received intravenous aciclovir, resulting in significant improvement within 48 hours. This case highlights the importance of early diagnosis and treatment, particularly when confirmatory tests are not available. The report discusses the clinical presentation of EH, which includes vesicular lesions, fever, and rapid progression. The differential diagnosis includes chickenpox, impetigo, eczema vaccinatum, and contact dermatitis. Understanding the epidemiology and pathogenesis of EH, especially in relation to AD, is crucial for effective management. The case also introduces a novel hypothesis linking structural protein alterations to immune dysfunction in EH, suggesting a need for further research. Acyclovir remains the gold standard for treating EH, and timely intervention is essential. This case underscores the necessity of a diagnostic algorithm in the absence of guidelines and highlights the role of IgM serology and clinical judgment in managing suspected EH cases.

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The non-structural protein (nsP2 & nsP3) of the CHIKV is responsible for the transmission of viral infection. The main role of nsp is involved in the transcription process at an early stage of the infection. In this work, authors have studied the impact of nsP2 and nsP3 of CHIKV on hormones present in the human body using a computational approach. The ten hormones of chemical properties such as 4-Androsterone-2,17-dione, aldosterone, androsterone, corticosterone, cortisol, cortisone, estradiol, estrone, progesterone and testosterone were taken as a potency. From the molecular docking, the binding energy of the complexes is estimated, and cortisone was found to be the highest negative binding energy (-6.57 kcal/mol) with the nsP2 protease and corticosterone with the nsP3 protease (-6.47 kcal/mol). This is based on the interactions between hormones and NsP2/NsP3, which are types of noncovalent intermolecular interactions categorized into three types: electrostatic interactions, van der Waals interactions, and hydrogen-bonding. To validate the docking results, molecular dynamics simulations and MM-GBSA methods were performed. The change in enthalpy, entropy, and free energy were calculated using MM-GBSA methods. The nsP2 and nsP3 protease of CHIKV interact strongly with the cortisone and corticosterone with free energy changes of -20.55 & -36.08 kcal/mol, respectively.

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Introduction: Bluetongue (BT) poses a significant threat to the livestock industry, affecting various animal species and resulting in substantial economic losses. The existence of numerous BT virus (BTV) serotypes has hindered control efforts, highlighting the need for broad-spectrum vaccines. Methodology: In this study, we evaluated the conserved amino acid sequences within key non-structural (NS) proteins of BTV and identified numerous highly conserved murine- and bovine-specific MHC class I-restricted (MHC-I) CD8+ and MHC-II-restricted CD4+ epitopes. We then screened these conserved epitopes for antigenicity, allergenicity, toxicity, and solubility. Using these epitopes, we developed in silico-based broad-spectrum multiepitope vaccines with Toll-like receptor (TLR-4) agonists. The predicted proinflammatory cytokine response was assessed in silico using the C-IMMSIM server. Structural modeling and refinement were achieved using Robetta and GalaxyWEB servers. Finally, we assessed the stability of the docking complexes through extensive 100-nanosecond molecular dynamics simulations before considering the vaccines for codon optimization and in silico cloning. Results: We found many epitopes that meet these criteria within NS1 and NS2 proteins and developed in silico broad-spectrum vaccines. The immune simulation studies revealed that these vaccines induce high levels of IFN-γ and IL-2 in the vaccinated groups. Protein-protein docking analysis demonstrated promising epitopes with strong binding affinities to TLR-4. The docked complexes were stable, with minimal Root Mean Square Deviation and Root Mean Square Fluctuation values. Finally, the in silico-cloned plasmids have high % of GC content with > 0.8 codon adaptation index, suggesting they are suitable for expressing the protein vaccines in prokaryotic system. Discussion: These next-generation vaccine designs are promising and warrant further investigation in wet lab experiments to assess their immunogenicity, safety, and efficacy for practical application in livestock. Our findings offer a robust framework for developing a comprehensive, broad-spectrum vaccine, potentially revolutionizing BT control and prevention strategies in the livestock industry.

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The Alphavirus genus includes viruses that cause encephalitis due to neuroinvasion and viruses that cause arthritis due to acute and chronic inflammation. There is no approved therapeutic for alphavirus infections, but significant efforts are ongoing, more so in recent years, to develop vaccines and therapeutics for alphavirus infections. This review article highlights some of the major advances made so far to identify small molecules that can selectively target the structural and the nonstructural proteins in alphaviruses with the expectation that persistent investigation of an increasingly expanding chemical space through a variety of structure-based design and high-throughput screening strategies will yield candidate drugs for clinical studies. While most of the works discussed are still in the early discovery to lead optimization stages, promising avenues remain for drug development against this family of viruses.

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A recombinant Ross River virus (RRV) that contains the fluorescent protein mCherry fused to the non-structural protein 3 (nsP3) was constructed, which allowed real-time imaging of viral replication. RRV-mCherry contained either the natural opal stop codon after the nsP3 gene or was constructed without a stop codon. The mCherry fusion protein did not interfere with the viral life cycle and deletion of the stop codon did not change the replication capacity of RRV-mCherry. Comparison of RRV-mCherry and chikungunya virus-mCherry infections, however, showed a cell type-dependent delay in RRV-mCherry replication in HEK 293T cells. This delay was not caused by differences in cell entry, but rather by an impeded nsP expression caused by the RRV inhibitor ZAP (zinc finger CCCH-Type, antiviral 1). The data indicate that viral replication of alphaviruses is cell-type dependent, and might be unique for each alphavirus.

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Fowl adenovirus serotype 4 (FAdV-4) is highly pathogenic to broilers aged 3 to 5 weeks and has caused considerable economic loss in the poultry industry worldwide. FAdV-4 is the causative agent of hydropericardium-hepatitis syndrome (HHS) or hydropericardium syndrome (HPS). The virus targets mainly the liver, and HPS symptoms are observed in infected chickens. This disease was first reported in Pakistan but has now spread worldwide, and over time, various deletions in the FAdV genome and mutations in its major structural proteins have been detected. This review provides detailed information about FAdV-4 genome organization, physiological features, epidemiology, coinfection with other viruses, and host immune suppression. Moreover, we investigated the role and functions of important structural proteins in FAdV-4 pathogenesis. Finally, the potential regulatory effects of FAdV-4 infection on ncRNAs are also discussed.

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The biological activity of structural HIV-1 proteins is not limited to ensuring a productive viral infection but also interferes with cellular homeostasis through intra- and extracellular signaling activation. This interference induces genomic instability, increases the lifespan of the infected cell by inhibiting apoptosis, and subverts cell senescence, resulting in unrestricted cell proliferation. HIV structural proteins are present in a soluble form in the lymphoid tissues and blood of infected individuals, even without active viral replication. The HIV matrix protein p17, the envelope glycoprotein gp120, the transenvelope protein gp41, and the capsid protein p24 interact with immune cells and deregulate the biological activity of the immune system. The biological activity of HIV structural proteins is also demonstrated in endothelial cells and some tumor cell lines, confirming the ability of viral proteins to promote cell proliferation and cancer progression, even in the absence of active viral replication. This review corroborates the hypothesis that HIV structural proteins, by interacting with different cell types, contribute to creating a microenvironment that is favorable to the evolution of cancerous pathologies not classically related to AIDS.

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The foot-and-mouth disease virus is a highly contagious and economically devastating virus of cloven-hooved animals, including cattle, buffalo, sheep, and goats, causing reduced animal productivity and posing international trade restrictions. For decades, chemically inactivated vaccines have been serving as the most effective strategy for the management of foot-and-mouth disease. Inactivated vaccines are commercially produced in cell culture systems, which require successful propagation and adaptation of field isolates, demanding a high cost and laborious time. Cell culture adaptation is chiefly indebted to amino acid substitutions in surface-exposed capsid proteins, altering the necessity of RGD-dependent receptors to heparan sulfate macromolecules for virus binding. Several amino acid substations in VP1, VP2, and VP3 capsid proteins of FMDV, both at structural and functional levels, have been characterized previously. This literature review combines frequently reported amino acid substitutions in virus capsid proteins, their critical roles in virus adaptation, and functional characterization of the substitutions. Furthermore, this data can facilitate molecular virologists to develop new vaccine strains against the foot-and-mouth disease virus, revolutionizing vaccinology via reverse genetic engineering and synthetic biology.

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Foot-and-mouth disease (FMD) is a contagious viral disease of cloven-footed animals. Immunization with inactivated virus vaccine is effective to control the disease. Six-monthly vaccination regimen in endemic regions has proven to be effective. To enable the differentiation of infected animals from those vaccinated, non-structural proteins (NSPs) are excluded during vaccine production. While the antibodies to structural proteins (SPs) could be observed both in vaccinated and infected animals, NSP antibodies are detectable only in natural infection. Quality control assays that detect NSPs in vaccine antigen preparations, are thus vital in the FMD vaccine manufacturing process. In this study, we designed a chemiluminescence dot blot assay to detect the 3A and 3B NSPs of FMDV. It is sensitive enough to detect up to 20 ng of the NSP, and exhibited specificity as it does not react with the viral SPs. This cost-effective assay holds promise in quality control assessment in FMD vaccine manufacturing.

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African swine fever (ASF) is a highly contagious acute hemorrhagic viral disease, with the mortality rate of up to 100 % in domestic pigs. In recent years, ASF outbreaks have caused huge economic losses in numerous countries and regions, especially in Asia. Therefore, there is a pressing need to develop safe and effective vaccines against infection of the causative pathogen, African swine fever virus (ASFV). ASFV contains a large genome composed of double-stranded DNA with a size of 170-194 kb, which encodes nearly 200 viral proteins. Understanding the function of these complex genes/proteins and their roles in the generation of protective immunity will help in the development of ASFV vaccines. In this article, the gene/protein-based vaccine candidate are summarized, and the structural proteins which have been previously reported to protect animals from the virus challenge were emphatically described.

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Chikungunya virus (CHIKV) is a single positive-stranded RNA virus of the Togaviridae family and Alphavirus genus, with a typical lipid bilayer envelope structure, and is the causative agent of human chikungunya fever (CHIKF). The U.S. Food and Drug Administration has recently approved the first chikungunya vaccine, Ixchiq; however, vaccination rates are low, and CHIKF is prevalent owing to its periodic outbreaks. Thus, developing effective anti-CHIKV drugs in clinical settings is imperative. Viral proteins encoded by the CHIKV genome play vital roles in all stages of infection, and developing therapeutic agents that target these CHIKV proteins is an effective strategy to improve CHIKF treatment efficacy and reduce mortality rates. Therefore, in the present review article, we aimed to investigate the basic structure, function, and replication cycle of CHIKV and comprehensively outline the current status and future advancements in anti-CHIKV drug development, specifically targeting nonstructural (ns) proteins, including nsP1, nsP2, nsP3, and nsP4 and structural proteins such as capsid (C), E3, E2, 6K, and E1.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third human coronavirus to cause acute respiratory distress syndrome (ARDS) and contains four structural proteins: spike, envelope, membrane, and nucleocapsid. An increasing number of studies have demonstrated that all four structural proteins of SARS-CoV-2 are capable of causing lung injury, even without the presence of intact virus. Therefore, the topic of SARS-CoV-2 structural protein-evoked lung injury warrants more attention. In the current article, we first synopsize the structural features of SARS-CoV-2 structural proteins. Second, we discuss the mechanisms for structural protein-induced inflammatory responses in vitro. Finally, we list the findings that indicate structural proteins themselves are toxic and sufficient to induce lung injury in vivo. Recognizing mechanisms of lung injury triggered by SARS-CoV-2 structural proteins may facilitate the development of targeted modalities in treating COVID-19.

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This book chapter presents a concise overview of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. It explores viral classification based on morphology and nucleic acid composition with a focus on DNA and RNA viruses, the SARS-CoV-2 structure including the structural as well as nonstructural proteins in detail, and the viral replication mechanisms. The chapter then delves into the characteristics and diversity of coronaviruses, particularly SARS-CoV-2, highlighting its similarities with other beta-coronaviruses. The replication and transcription complex, RNA elongation, and capping, as well as the role of accessory proteins in viral replication and modulation of the host immune response is discussed extensively.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-stranded RNA virus that sits at the centre of the recent global pandemic. As a member of the coronaviridae family of viruses, it shares features such as a very large genome (>30 kb) that is replicated in a purpose-built replication organelle. Biogenesis of the replication organelle requires significant and concerted rearrangement of the endoplasmic reticulum membrane, a job that is carried out by a group of integral membrane non-structural proteins (NSP3, 4 and 6) expressed by the virus along with a host of viral replication enzymes and other factors that support transcription and replication. The primary sites for RNA replication within the replication organelle are double membrane vesicles (DMVs). The small size of DMVs requires generation of high membrane curvature, as well as stabilization of a double-membrane arrangement, but the mechanisms that underlie DMV formation remain elusive. In this review, we discuss recent breakthroughs in our understanding of the molecular basis for membrane rearrangements by coronaviruses. We incorporate established models of NSP3-4 protein-protein interactions to drive double membrane formation, and recent data highlighting the roles of lipid composition and host factor proteins (e.g. reticulons) that influence membrane curvature, to propose a revised model for DMV formation in SARS-CoV-2.

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Although COVID-19 transmission has been reduced by the advent of vaccinations and a variety of rapid monitoring techniques, the SARS-CoV-2 virus itself has shown a remarkable ability to mutate and persist. With this long track record of immune escape, researchers are still exploring prophylactic treatments to curtail future SARS-CoV-2 variants. Specifically, much focus has been placed on the antiviral lectin Griffithsin in preventing spike protein-mediated infection via the hACE2 receptor (direct infection). However, an oft-overlooked aspect of SARS-CoV-2 infection is viral capture by attachment receptors such as DC-SIGN, which is thought to facilitate the initial stages of COVID-19 infection in the lung tissue (called trans-infection). In addition, while immune escape is dictated by mutations in the spike protein, coronaviral virions also incorporate M, N, and E structural proteins within the particle. In this paper, we explored how several structural facets of both the SARS-CoV-2 virion and the antiviral lectin Griffithsin can affect and attenuate the infectivity of SARS-CoV-2 pseudovirus. We found that Griffithsin was a better inhibitor of hACE2-mediated direct infection when the coronaviral M protein is present compared to when it is absent (possibly providing an explanation regarding why Griffithsin shows better inhibition against authentic SARS-CoV-2 as opposed to pseudotyped viruses, which generally do not contain M) and that Griffithsin was not an effective inhibitor of DC-SIGN-mediated trans-infection. Furthermore, we found that DC-SIGN appeared to mediate trans-infection exclusively via binding to the SARS-CoV-2 spike protein, with no significant effect observed when other viral proteins (M, N, and/or E) were present. These results provide etiological data that may help to direct the development of novel antiviral treatments, either by leveraging Griffithsin binding to the M protein as a novel strategy to prevent SARS-CoV-2 infection or by narrowing efforts to inhibit trans-infection to focus on DC-SIGN binding to SARS-CoV-2 spike protein.

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This study examines an unexplored aspect of SARS-CoV-2 entry into host cells, which is widely understood to occur via the viral spike (S) protein's interaction with human ACE2-associated proteins. While vaccines and inhibitors targeting this mechanism are in use, they may not offer complete protection against reinfection. Hence, we investigate putative receptors and their cofactors. Specifically, we propose CD46, a human membrane cofactor protein, as a potential putative receptor and explore its role in cellular invasion, acting possibly as a cofactor with other viral structural proteins. Employing computational techniques, we created full-size 3D models of human CD46 and four key SARS-CoV-2 structural proteins-EP, MP, NP, and SP. We further developed 3D models of CD46 complexes interacting with these proteins. The primary aim is to pinpoint the likely interaction domains between CD46 and these structural proteins to facilitate the identification of molecules that can block these interactions, thus offering a foundation for novel pharmacological treatments for SARS-CoV-2 infection.

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Methylene blue has multiple antiviral properties against Severe Acute Respiratory Syndrome-related Coronavirus 2 (SARS-CoV-2). The ability of methylene blue to inhibit different stages of the virus life cycle, both in light-independent and photodynamic processes, is used in clinical practice. At the same time, the molecular aspects of the interactions of methylene blue with molecular components of coronaviruses are not fully understood. Here, we use Brownian dynamics to identify methylene blue binding sites on the SARS-CoV-2 envelope. The local lipid and protein composition of the coronavirus envelope plays a crucial role in the binding of this cationic dye. Viral structures targeted by methylene blue include the S and E proteins and negatively charged lipids. We compare the obtained results with known experimental data on the antiviral effects of methylene blue to elucidate the molecular basis of its activity against coronaviruses.

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BACKGROUND: Dengue, a mosquito-borne viral disease spread by the dengue virus (DENV), has become one of the most alarming health issues in the global scenario in recent days. The risk of infection by DENV is mostly high in tropical and subtropical areas of the world. The mortality rate of patients affected with DENV is ever-increasing, mainly due to a lack of anti-dengue viral-specific synthetic drug components. INTRODUCTION: Repurposing synthetic drugs has been an effective tool in combating several pathogens, including DENV. However, only the Dengvaxia vaccine has been developed so far to fight against the deadly disease despite the grave situation, mainly because of the limitations of understanding the actual pathogenicity of the disease. METHODS: To address this particular issue and explore the actual disease pathobiology, several potential targets, like three structural proteins and seven non-structural (NS) proteins, along with their inhibitors of synthetic and natural origin, have been screened using docking simulation. RESULTS: Exploration of these targets, along with their inhibitors, has been extensively studied in culmination with molecular docking-based screening to potentiate the treatment. CONCLUSION: These screened inhibitors could possibly be helpful for the designing of new congeneric potential compounds to combat dengue fever and its complications.

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Promyelocytic leukemia (PML) protein constitutes an indispensable element within PML-nuclear bodies (PML-NBs), playing a pivotal role in the regulation of multiple cellular functions while coordinating the innate immune response against viral invasions. Simultaneously, numerous viruses elude immune detection by targeting PML-NBs. Japanese encephalitis virus (JEV) is a flavivirus that causes Japanese encephalitis, a severe neurological disease that affects humans and animals. However, the mechanism through which JEV evades immunity via PML-NBs has been scarcely investigated. In the present study, PK15 cells were infected with JEV, and the quantity of intracellular PML-NBs was enumerated. The immunofluorescence results indicated that the number of PML-NBs was significantly reduced in JEV antigen-positive cells compared to viral antigen-negative cells. Subsequently, ten JEV proteins were cloned and transfected into PK15 cells. The results revealed that JEV non-structural proteins, NS2B, NS3, NS4A, NS4B, and NS5, significantly diminished the quantity of PML-NBs. Co-transfection was performed with the five JEV proteins and various porcine PML isoforms. The results demonstrated that NS2B colocalized with PML4 and PML5, NS4A colocalized with PML1 and PML4, NS4B colocalized with PML1, PML3, PML4, and PML5, while NS3 and NS5 interacted with all five PML isoforms. Furthermore, ectopic expression of PML isoforms confirmed that PML1, PML3, PML4, and PML5 inhibited JEV replication. These findings suggest that JEV disrupts the structure of PML-NBs through interaction with PML isoforms, potentially leading to the attenuation of the host's antiviral immune response.

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