Antiviral activity of berberine.

Plants are a rich source of new antiviral, pharmacologically active agents. The naturally occurring plant alkaloid berberine (BBR) is one of the phytochemicals with a broad range of biological activity, including anticancer, anti-inflammatory and antiviral activity. BBR targets different steps in the viral life cycle and is thus a good candidate for use in novel antiviral drugs and therapies. It has been shown that BBR reduces virus replication and targets specific interactions between the virus and its host. BBR intercalates into DNA and inhibits DNA synthesis and reverse transcriptase activity. It inhibits replication of herpes simplex virus (HSV), human cytomegalovirus (HCMV), human papillomavirus (HPV), and human immunodeficiency virus (HIV). This isoquinoline alkaloid has the ability to regulate the MEK-ERK, AMPK/mTOR, and NF-κB signaling pathways, which are necessary for viral replication. Furthermore, it has been reported that BBR supports the host immune response, thus leading to viral clearance. In this short review, we focus on the most recent studies on the antiviral properties of berberine and its derivatives, which might be promising agents to be considered in future studies in the fight against the current pandemic SARS-CoV-2, the virus that causes COVID-19.

A Broad Antiviral Strategy: Inhibitors of Human DHODH Pave the Way for Host-Targeting Antivirals against Emerging and Re-Emerging Viruses.

New strategies to rapidly develop broad-spectrum antiviral therapies are urgently required for emerging and re-emerging viruses. Host-targeting antivirals (HTAs) that target the universal host factors necessary for viral replication are the most promising approach, with broad-spectrum, foresighted function, and low resistance. We and others recently identified that host dihydroorotate dehydrogenase (DHODH) is one of the universal host factors essential for the replication of many acute-infectious viruses. DHODH is a rate-limiting enzyme catalyzing the fourth step in de novo pyrimidine synthesis. Therefore, it has also been developed as a therapeutic target for many diseases relying on cellular pyrimidine resources, such as cancers, autoimmune diseases, and viral or bacterial infections. Significantly, the successful use of DHODH inhibitors (DHODHi) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection further supports the application prospects. This review focuses on the advantages of HTAs and the antiviral effects of DHODHi with clinical applications. The multiple functions of DHODHi in inhibiting viral replication, stimulating ISGs expression, and suppressing cytokine storms make DHODHi a potent strategy against viral infection.

Broad-Spectrum Antivirals and Antiviral Drug Combinations.

Viral diseases consistently pose a substantial economic and public health burden worldwide [...].

Polysaccharides and Their Derivatives as Potential Antiviral Molecules.

In the current context of the COVID-19 pandemic, it appears that our scientific resources and the medical community are not sufficiently developed to combat rapid viral spread all over the world. A number of viruses causing epidemics have already disseminated across the world in the last few years, such as the dengue or chinkungunya virus, the Ebola virus, and other coronavirus families such as Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV). The outbreaks of these infectious diseases have demonstrated the difficulty of treating an epidemic before the creation of vaccine. Different antiviral drugs already exist. However, several of them cause side effects or have lost their efficiency because of virus mutations. It is essential to develop new antiviral strategies, but ones that rely on more natural compounds to decrease the secondary effects. Polysaccharides, which have come to be known in recent years for their medicinal properties, including antiviral activities, are an excellent alternative. They are essential for the metabolism of plants, microorganisms, and animals, and are directly extractible. Polysaccharides have attracted more and more attention due to their therapeutic properties, low toxicity, and availability, and seem to be attractive candidates as antiviral drugs of tomorrow.

Recent Advances in Metal-Based Antimicrobial Coatings for High-Touch Surfaces.

International interest in metal-based antimicrobial coatings to control the spread of bacteria, fungi, and viruses via high contact human touch surfaces are growing at an exponential rate. This interest recently reached an all-time high with the outbreak of the deadly COVID-19 disease, which has already claimed the lives of more than 5 million people worldwide. This global pandemic has highlighted the major role that antimicrobial coatings can play in controlling the spread of deadly viruses such as SARS-CoV-2 and scientists and engineers are now working harder than ever to develop the next generation of antimicrobial materials. This article begins with a review of three discrete microorganism-killing phenomena of contact-killing surfaces, nanoprotrusions, and superhydrophobic surfaces. The antimicrobial properties of metals such as copper (Cu), silver (Ag), and zinc (Zn) are reviewed along with the effects of combining them with titanium dioxide (TiO2) to create a binary or ternary contact-killing surface coatings. The self-cleaning and bacterial resistance of purely structural superhydrophobic surfaces and the potential of physical surface nanoprotrusions to damage microbial cells are then considered. The article then gives a detailed discussion on recent advances in attempting to combine these individual phenomena to create super-antimicrobial metal-based coatings with binary or ternary killing potential against a broad range of microorganisms, including SARS-CoV-2, for high-touch surface applications such as hand rails, door plates, and water fittings on public transport and in healthcare, care home and leisure settings as well as personal protective equipment commonly used in hospitals and in the current COVID-19 pandemic.

Metadichol®: A Novel Nanolipid Formulation That Inhibits SARS-CoV-2 and a Multitude of Pathological Viruses In Vitro.

Increasing outbreaks of new pathogenic viruses have promoted the exploration of novel alternatives to time-consuming vaccines. Thus, it is necessary to develop a universal approach to halt the spread of new and unknown viruses as they are discovered. One such promising approach is to target lipid membranes, which are common to all viruses and bacteria. The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has reaffirmed the importance of interactions between the virus envelope and the host cell plasma membrane as a critical mechanism of infection. Metadichol®, a nanolipid emulsion of long-chain alcohols, has been demonstrated as a strong candidate that inhibits the proliferation of SARS-CoV-2. Naturally derived substances, such as long-chain saturated lipid alcohols, reduce viral infectivity, including that of coronaviruses (such as SARS-CoV-2) by modifying their lipid-dependent attachment mechanism to human host cells. The receptor ACE2 mediates the entry of SARS-CoV-2 into the host cells, whereas the serine protease TMPRSS2 primes the viral S protein. In this study, Metadichol® was found to be 270 times more potent an inhibitor of TMPRSS2 (EC50 = 96 ng/mL) than camostat mesylate (EC50 = 26000 ng/mL). Additionally, it inhibits ACE with an EC50 of 71 ng/mL, but it is a very weak inhibitor of ACE2 at an EC50 of 31 µg/mL. Furthermore, the live viral assay performed in Caco-2 cells revealed that Metadichol® inhibits SARS-CoV-2 replication at an EC90 of 0.16 µg/mL. Moreover, Metadichol® had an EC90 of 0.00037 µM, making it 2081 and 3371 times more potent than remdesivir (EC50 = 0.77 µM) and chloroquine (EC50 = 1.14 µM), respectively.

Antiviral Strategies Using Natural Source-Derived Sulfated Polysaccharides in the Light of the COVID-19 Pandemic and Major Human Pathogenic Viruses.

Only a mere fraction of the huge variety of human pathogenic viruses can be targeted by the currently available spectrum of antiviral drugs. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the urgent need for molecules that can be deployed quickly to treat novel, developing or re-emerging viral infections. Sulfated polysaccharides are found on the surfaces of both the susceptible host cells and the majority of human viruses, and thus can play an important role during viral infection. Such polysaccharides widely occurring in natural sources, specifically those converted into sulfated varieties, have already proved to possess a high level and sometimes also broad-spectrum antiviral activity. This antiviral potency can be determined through multifold molecular pathways, which in many cases have low profiles of cytotoxicity. Consequently, several new polysaccharide-derived drugs are currently being investigated in clinical settings. We reviewed the present status of research on sulfated polysaccharide-based antiviral agents, their structural characteristics, structure-activity relationships, and the potential of clinical application. Furthermore, the molecular mechanisms of sulfated polysaccharides involved in viral infection or in antiviral activity, respectively, are discussed, together with a focus on the emerging methodology contributing to polysaccharide-based drug development.

JAK-STAT Pathway: A Novel Target to Tackle Viral Infections.

Modulation of the antiviral innate immune response has been proposed as a putative cellular target for the development of novel pan-viral therapeutic strategies. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is especially relevant due to its essential role in the regulation of local and systemic inflammation in response to viral infections, being, therefore, a putative therapeutic target. Here, we review the extraordinary diversity of strategies that viruses have evolved to interfere with JAK-STAT signaling, stressing the relevance of this pathway as a putative antiviral target. Moreover, due to the recent remarkable progress on the development of novel JAK inhibitors (JAKi), the current knowledge on its efficacy against distinct viral infections is also discussed. JAKi have a proven efficacy against a broad spectrum of disorders and exhibit safety profiles comparable to biologics, therefore representing good candidates for drug repurposing strategies, including viral infections.

Synergistic Interferon-Alpha-Based Combinations for Treatment of SARS-CoV-2 and Other Viral Infections.

BACKGROUND: There is an urgent need for new antivirals with powerful therapeutic potential and tolerable side effects. METHODS: Here, we tested the antiviral properties of interferons (IFNs), alone and with other drugs in vitro. RESULTS: While IFNs alone were insufficient to completely abolish replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), IFNα, in combination with remdesivir, EIDD-2801, camostat, cycloheximide, or convalescent serum, proved to be more effective. Transcriptome and metabolomic analyses revealed that the IFNα-remdesivir combination suppressed SARS-CoV-2-mediated changes in Calu-3 cells and lung organoids, although it altered the homeostasis of uninfected cells and organoids. We also demonstrated that IFNα combinations with sofosbuvir, telaprevir, NITD008, ribavirin, pimodivir, or lamivudine were effective against HCV, HEV, FLuAV, or HIV at lower concentrations, compared to monotherapies. CONCLUSIONS: Altogether, our results indicated that IFNα can be combined with drugs that affect viral RNA transcription, protein synthesis, and processing to make synergistic combinations that can be attractive targets for further pre-clinical and clinical development against emerging and re-emerging viral infections.

Facilitating Antiviral Drug Discovery Using Genetic and Evolutionary Knowledge.

Over the course of human history, billions of people worldwide have been infected by various viruses. Despite rapid progress in the development of biomedical techniques, it is still a significant challenge to find promising new antiviral targets and drugs. In the past, antiviral drugs mainly targeted viral proteins when they were used as part of treatment strategies. Since the virus mutation rate is much faster than that of the host, such drugs feature drug resistance and narrow-spectrum antiviral problems. Therefore, the targeting of host molecules has gradually become an important area of research for the development of antiviral drugs. In recent years, rapid advances in high-throughput sequencing techniques have enabled numerous genetic studies (such as genome-wide association studies (GWAS), clustered regularly interspersed short palindromic repeats (CRISPR) screening, etc.) for human diseases, providing valuable genetic and evolutionary resources. Furthermore, it has been revealed that successful drug targets exhibit similar genetic and evolutionary features, which are of great value in identifying promising drug targets and discovering new drugs. Considering these developments, in this article the authors propose a host-targeted antiviral drug discovery strategy based on knowledge of genetics and evolution. We first comprehensively summarized the genetic, subcellular location, and evolutionary features of the human genes that have been successfully used as antiviral targets. Next, the summarized features were used to screen novel druggable antiviral targets and to find potential antiviral drugs, in an attempt to promote the discovery of new antiviral drugs.

Imaging of Virus-Infected Cells with Soft X-ray Tomography.

Viruses are obligate parasites that depend on a host cell for replication and survival. Consequently, to fully understand the viral processes involved in infection and replication, it is fundamental to study them in the cellular context. Often, viral infections induce significant changes in the subcellular organization of the host cell due to the formation of viral factories, alteration of cell cytoskeleton and/or budding of newly formed particles. Accurate 3D mapping of organelle reorganization in infected cells can thus provide valuable information for both basic virus research and antiviral drug development. Among the available techniques for 3D cell imaging, cryo-soft X-ray tomography stands out for its large depth of view (allowing for 10 µm thick biological samples to be imaged without further thinning), its resolution (about 50 nm for tomographies, sufficient to detect viral particles), the minimal requirements for sample manipulation (can be used on frozen, unfixed and unstained whole cells) and the potential to be combined with other techniques (i.e., correlative fluorescence microscopy). In this review we describe the fundamentals of cryo-soft X-ray tomography, its sample requirements, its advantages and its limitations. To highlight the potential of this technique, examples of virus research performed at BL09-MISTRAL beamline in ALBA synchrotron are also presented.

Antiviral peptide engineering for targeting membrane-enveloped viruses: Recent progress and future directions.

Membrane-enveloped viruses are a major cause of global health challenges, including recent epidemics and pandemics. This mini-review covers the latest efforts to develop membrane-targeting antiviral peptides that inhibit enveloped viruses by 1) preventing virus-cell fusion or 2) disrupting the viral membrane envelope. The corresponding mechanisms of antiviral activity are discussed along with peptide engineering strategies to modulate membrane-peptide interactions in terms of potency and selectivity. Application examples are presented demonstrating how membrane-targeting antiviral peptides are useful therapeutics and prophylactics in animal models, while a stronger emphasis on biophysical concepts is proposed to refine mechanistic understanding and support potential clinical translation.

Short Peptides Make a Big Difference: The Role of Botany-Derived AMPs in Disease Control and Protection of Human Health.

Botany-derived antimicrobial peptides (BAMPs), a class of small, cysteine-rich peptides produced in plants, are an important component of the plant immune system. Both in vivo and in vitro experiments have demonstrated their powerful antimicrobial activity. Besides in plants, BAMPs have cross-kingdom applications in human health, with toxic and/or inhibitory effects against a variety of tumor cells and viruses. With their diverse molecular structures, broad-spectrum antimicrobial activity, multiple mechanisms of action, and low cytotoxicity, BAMPs provide ideal backbones for drug design, and are potential candidates for plant protection and disease treatment. Lots of original research has elucidated the properties and antimicrobial mechanisms of BAMPs, and characterized their surface receptors and in vivo targets in pathogens. In this paper, we review and introduce five kinds of representative BAMPs belonging to the pathogenesis-related protein family, dissect their antifungal, antiviral, and anticancer mechanisms, and forecast their prospects in agriculture and global human health. Through the deeper understanding of BAMPs, we provide novel insights for their applications in broad-spectrum and durable plant disease prevention and control, and an outlook on the use of BAMPs in anticancer and antiviral drug design.

Potential of an Eco-Sustainable Probiotic-Cleaning Formulation in Reducing Infectivity of Enveloped Viruses.

The COVID-19 pandemic has deeply influenced sanitization procedures, and high-level disinfection has been massively used to prevent SARS-CoV-2 spread, with potential negative impact on the environment and on the threat of antimicrobial resistance (AMR). Aiming to overcome these concerns, yet preserving the effectiveness of sanitization against enveloped viruses, we assessed the antiviral properties of the Probiotic Cleaning Hygiene System (PCHS), an eco-sustainable probiotic-based detergent previously proven to stably abate pathogen contamination and AMR. PCHS (diluted 1:10, 1:50 and 1:100) was tested in comparison to common disinfectants (70% ethanol and 0.5% sodium hypochlorite), in suspension and carrier tests, according with the European UNI EN 14476:2019 and UNI EN 16777:2019 standards. Human alpha- and beta-coronaviruses hCoV-229E and SARS-CoV-2, human herpesvirus type 1, human and animal influenza viruses, and vaccinia virus were included in the study. The results showed that PCHS was able to inactivate 99.99% of all tested viruses within 1-2 h of contact, both in suspension and on surface. Notably, while control disinfectants became inactive within 2 h after application, the PCHS antiviral action persisted up to 24 h post-application, suggesting that its use may effectively allow a continuous prevention of virus spread via contaminated environment, without worsening environmental pollution and AMR concern.

Unravelling the Immunomodulatory Effects of Viral Ion Channels, towards the Treatment of Disease.

The current COVID-19 pandemic has highlighted the need for the research community to develop a better understanding of viruses, in particular their modes of infection and replicative lifecycles, to aid in the development of novel vaccines and much needed anti-viral therapeutics. Several viruses express proteins capable of forming pores in host cellular membranes, termed "Viroporins". They are a family of small hydrophobic proteins, with at least one amphipathic domain, which characteristically form oligomeric structures with central hydrophilic domains. Consequently, they can facilitate the transport of ions through the hydrophilic core. Viroporins localise to host membranes such as the endoplasmic reticulum and regulate ion homeostasis creating a favourable environment for viral infection. Viroporins also contribute to viral immune evasion via several mechanisms. Given that viroporins are often essential for virion assembly and egress, and as their structural features tend to be evolutionarily conserved, they are attractive targets for anti-viral therapeutics. This review discusses the current knowledge of several viroporins, namely Influenza A virus (IAV) M2, Human Immunodeficiency Virus (HIV)-1 Viral protein U (Vpu), Hepatitis C Virus (HCV) p7, Human Papillomavirus (HPV)-16 E5, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Open Reading Frame (ORF)3a and Polyomavirus agnoprotein. We highlight the intricate but broad immunomodulatory effects of these viroporins and discuss the current antiviral therapies that target them; continually highlighting the need for future investigations to focus on novel therapeutics in the treatment of existing and future emergent viruses.

Organic Photo-antimicrobials: Principles, Molecule Design, and Applications.

The emergence of multi-drug-resistant pathogens threatens the healthcare systems world-wide. Recent advances in phototherapy (PT) approaches mediated by photo-antimicrobials (PAMs) provide new opportunities for the current serious antibiotic resistance. During the PT treatment, reactive oxygen species or heat produced by PAMs would react with the cell membrane, consequently leaking cytoplasm components and effectively eradicating different pathogens like bacteria, fungi, viruses, and even parasites. This Perspective will concentrate on the development of different organic photo-antimicrobials (OPAMs) and their application as practical therapeutic agents into therapy for local infections, wound dressings, and removal of biofilms from medical devices. We also discuss how to design highly efficient OPAMs by modifying the chemical structure or conjugating with a targeting component. Moreover, this Perspective provides a discussion of the general challenges and direction for OPAMs and what further needs to be done. It is hoped that through this overview, OPAMs can prosper and will be more widely used for microbial infections in the future, especially at a time when the global COVID-19 epidemic is getting more serious.

An Insight into Nanomedicinal Approaches to Combat Viral Zoonoses.

BACKGROUND: Emerging viral zoonotic diseases are one of the major obstacles to secure the "One Health" concept under the current scenario. Current prophylactic, diagnostic and therapeutic approaches often associated with certain limitations and thus proved to be insufficient for customizing rapid and efficient combating strategy against the highly transmissible pathogenic infectious agents leading to the disastrous socio-economic outcome. Moreover, most of the viral zoonoses originate from the wildlife and poor knowledge about the global virome database renders it difficult to predict future outbreaks. Thus, alternative management strategy in terms of improved prophylactic vaccines and their delivery systems; rapid and efficient diagnostics and effective targeted therapeutics are the need of the hour. METHODS: Structured literature search has been performed with specific keywords in bibliographic databases for the accumulation of information regarding current nanomedicine interventions along with standard books for basic virology inputs. RESULTS: Multi-arrayed applications of nanomedicine have proved to be an effective alternative in all the aspects regarding the prevention, diagnosis, and control of zoonotic viral diseases. The current review is focused to outline the applications of nanomaterials as anti-viral vaccines or vaccine/drug delivery systems, diagnostics and directly acting therapeutic agents in combating the important zoonotic viral diseases in the recent scenario along with their potential benefits, challenges and prospects to design successful control strategies. CONCLUSION: This review provides significant introspection towards the multi-arrayed applications of nanomedicine to combat several important zoonotic viral diseases.

Ethanol Susceptibility of SARS-CoV-2 and Other Enveloped Viruses.

Ethanol is an effective disinfectant against the novel coronavirus SARS-CoV-2. However, its effective concentration has not been shown, and we therefore analyzed the effects of different concentrations of ethanol on SARS-CoV-2. When SARS-CoV-2 was treated with varying ethanol concentrations and examined for changes in infectivity, the ethanol concentration at which 99% of the infectious titers were reduced was 24.1% (w/w) [29.3% (v/v)]. For reference, ethanol susceptibility was also examined with other envelope viruses, including influenza virus, vesicular stomatitis virus in the family Rhabdoviridae, and Newcastle disease virus in the family Paramyxoviridae, and the 99% inhibitory concentrations were found to be 28.8%(w/w) [34.8% (v/v)], 24.0% (w/w) [29.2% (v/v)], and 13.3% (w/w) [16.4% (v/v)], respectively. Some differences from SARS-CoV-2 were observed, but the differences were not significant. It was concluded that ethanol at a concentration of 30%(w/w) [36.2% (v/v)] almost completely inactivates SARS-CoV-2.

Exploring the potential usefulness of IgY for antiviral therapy: A current review.

Immunoglobulin yolk (IgY) is therapeutic antibodies presented in yolk eggs of birds, reptiles, and amphibians. These proteins produced by the immune system of the animal, are capable of neutralizing antigenic molecules, including viral antigens, fulfilling a role in the body defense. The specificity of these antibodies and the facility for their production, make these molecules capable of being used as tools for diagnosis and immunotherapy. Regarding this last aspect, it is common knowledge that the field of virology, is racing against time in the development of new drugs and vaccines to try to contain pandemics and local epidemics and, in counterproposal, avian antibodies are neutralizing molecules that can help in the control and spread of disease. These molecules have been explored for years and currently chicken eggs are produced in large quantities from the animal's immunization against a specific pathogen. Thus, on this subject, this review made a survey of these researches and presents a summary of all the successful cases and perspectives in the use of IgYs as tools for viral immunization.