Graphene-based materials as nanoplatforms for antiviral therapy and prophylaxis.

INTRODUCTION: The dramatic effects caused by viral diseases have prompted the search for effective therapeutic and preventive agents. In this context, 2D graphene-based nanomaterials (GBNs) have shown great potential for antiviral therapy, enabling the functionalization and/or decoration with biomolecules, metals and polymers, able to improve their interaction with viral nanoparticles. AREAS COVERED: This review summarizes the most recent advances of the antiviral research related to 2D GBNs, based on their antiviral mechanism of action. Their ability to inactivate viruses by inhibiting the entry inside cells, or through drug/gene delivery, or by stimulating the host immune response are here discussed. As reported, biological studies performed in vitro and/or in vivo allowed to demonstrate the antiviral activity of the developed GBNs, at different stages of the virus life cycle and the evaluation of their long-term toxicity. Other mechanisms closely related to the physicochemical properties of GBNs are also reported, demonstrating the potential of these materials for antiviral prophylaxis. EXPERT OPINION: GBNs represent valuable tools to fight emerging or reemerging viral infections. However, their translation into the clinic requires standardized scale-up procedures leading to the reliable and reproducible synthesis of these nanomaterials with suitable physicochemical properties, as well as more in-depth pharmacological and toxicological investigations. We believe that multidisciplinary approaches will give valuable solutions to overcome the encountered limitations in the application of GBNs in biomedical and clinical field.

Host Cell Proteases Involved in Human Respiratory Viral Infections and Their Inhibitors: A Review.

Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility to infection. Here we review the use of host cell proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe the various classes of proteases present in the respiratory tract, as well as elsewhere in the body, and incorporate the targeting of these proteases as therapeutic drugs for use in humans. Host cell proteases are also linked to the systemic spread of viruses and play important roles outside of the respiratory tract; therefore, we address how proteases affect viruses across the spectrum of infections that can occur in humans, intending to understand the extrapulmonary spread of SARS-CoV-2.

A closer look at mammalian antiviral condensates.

Several biomolecular condensates assemble in mammalian cells in response to viral infection. The most studied of these are stress granules (SGs), which have been proposed to promote antiviral innate immune signaling pathways, including the RLR-MAVS, the protein kinase R (PKR), and the OAS-RNase L pathways. However, recent studies have demonstrated that SGs either negatively regulate or do not impact antiviral signaling. Instead, the SG-nucleating protein, G3BP1, may function to perturb viral RNA biology by condensing viral RNA into viral-aggregated RNA condensates, thus explaining why viruses often antagonize G3BP1 or hijack its RNA condensing function. However, a recently identified condensate, termed double-stranded RNA-induced foci, promotes the activation of the PKR and OAS-RNase L antiviral pathways. In addition, SG-like condensates known as an RNase L-induced bodies (RLBs) have been observed during many viral infections, including SARS-CoV-2 and several flaviviruses. RLBs may function in promoting decay of cellular and viral RNA, as well as promoting ribosome-associated signaling pathways. Herein, we review these recent advances in the field of antiviral biomolecular condensates, and we provide perspective on the role of canonical SGs and G3BP1 during the antiviral response.

New technologies in therapeutic antibody development: The next frontier for treating infectious diseases.

Adaptive immunity to viral infections requires time to neutralize and clear viruses to resolve infection. Fast growing and pathogenic viruses are quickly established, are highly transmissible and cause significant disease burden making it difficult to mount effective responses, thereby prolonging infection. Antibody-based passive immunotherapies can provide initial protection during acute infection, assist in mounting an adaptive immune response, or provide protection for those who are immune suppressed or immune deficient. Historically, plasma-derived antibodies have demonstrated some success in treating diseases caused by viral pathogens; nonetheless, limitations in access to product and antibody titer reduce success of this treatment modality. Monoclonal antibodies (mAbs) have proven an effective alternative, as it is possible to manufacture highly potent and specific mAbs against viral targets on an industrial scale. As a result, innovative technologies to discover, engineer and manufacture specific and potent antibodies have become an essential part of the first line of treatment in pathogenic viral infections. However, a mAb targeting a specific epitope will allow escape variants to outgrow, causing new variant strains to become dominant and resistant to treatment with that mAb. Methods to mitigate escape have included combining mAbs into cocktails, creating bi-specific or antibody drug conjugates but these strategies have also been challenged by the potential development of escape mutations. New technologies in developing antibodies made as recombinant polyclonal drugs can integrate the strength of poly-specific antibody responses to prevent mutational escape, while also incorporating antibody engineering to prevent antibody dependent enhancement and direct adaptive immune responses.

Lectibodies as antivirals.

Growing concerns regarding the emergence of highly transmissible viral diseases highlight the urgent need to expand the repertoire of antiviral therapeutics. For this reason, new strategies for neutralizing and inhibiting these viruses are necessary. A promising approach involves targeting the glycans present on the surfaces of enveloped viruses. Lectins, known for their ability to recognize specific carbohydrate molecules, offer the potential for glycan-targeted antiviral strategies. Indeed, numerous studies have reported the antiviral effects of various lectins of both endogenous and exogenous origins. However, many lectins in their natural forms, are not suitable for use as antiviral therapeutics due to toxicity, other unfavorable pharmacological effects, and/or unreliable manufacturing sources. Therefore, improvements are crucial for employing lectins as effective antiviral therapeutics. A novel approach to enhance lectins' suitability as pharmaceuticals could be the generation of recombinant lectin-Fc fusion proteins, termed "lectibodies." In this review, we discuss the scientific rationale behind lectin-based antiviral strategies and explore how lectibodies could facilitate the development of new antiviral therapeutics. We will also share our perspective on the potential of these molecules to transcend their potential use as antiviral agents.

The use of proteins and peptides-based therapy in managing and preventing pathogenic viruses.

Therapeutic proteins have been employed for centuries and reached approximately 50 % of all drugs investigated. By 2023, they represented one of the top 10 largest-selling pharma products ($387.03 billion) and are anticipated to reach around $653.35 billion by 2030. Growth hormones, insulin, and interferon (IFN α, γ, and ß) are among the leading applied therapeutic proteins with a higher market share. Protein-based therapies have opened new opportunities to control various diseases, including metabolic disorders, tumors, and viral outbreaks. Advanced recombinant DNA biotechnology has offered the production of therapeutic proteins and peptides for vaccination, drugs, and diagnostic tools. Prokaryotic and eukaryotic expression host systems, including bacterial, fungal, animal, mammalian, and plant cells usually applied for recombinant therapeutic proteins large-scale production. However, several limitations face therapeutic protein production and applications at the commercial level, including immunogenicity, integrity concerns, protein stability, and protein degradation under different circumstances. In this regard, protein-engineering strategies such as PEGylation, glycol-engineering, Fc-fusion, albumin conjugation, and fusion, assist in increasing targeting, product purity, production yield, functionality, and the half-life of therapeutic protein circulation. Therefore, a comprehensive insight into therapeutic protein research and findings pave the way for their successful implementation, which will be discussed in the current review.

A comprehensive review on targeting cluster of differentiation: An attractive strategy for inhibiting viruses through host proteins.

Viral infections continue to pose a significant global public health threat. Targeting host proteins, such as cluster of differentiation (CD) macromolecules, may offer a promising alternative approach to developing antiviral treatments. CDs are cell-surface biological macromolecules mainly expressed on leukocytes that viruses can use to enter cells, thereby evading immune detection and promoting their replication. The manipulation of CDs by viruses may represent an effective and clever means of survival through the prolonged co-evolution of hosts and viruses. Targeting of CDs is anticipated to hinder the invasion of related viruses, modulate the body's immune system, and diminish the incidence of subsequent inflammation. They have become crucial for biomedical diagnosis, and some have been used as valuable tools for resisting viral infections. However, a summary of the structures and functions of CDs involved in viral infection is currently lacking. The development of drugs targeting these biological macromolecules is restricted both in terms of their availability and the number of compounds currently identified. This review provides a comprehensive analysis of the critical role of CD proteins in virus invasion and a list of relevant targeted antiviral agents, which will serve as a valuable reference for future research in this field.

A Reliable Multifaceted Solution against Foodborne Viral Infections: The Case of RiLK1 Decapeptide.

Food-borne transmission is a recognized route for many viruses associated with gastrointestinal, hepatic, or neurological diseases. Therefore, it is essential to identify new bioactive compounds with broad-spectrum antiviral activity to exploit innovative solutions against these hazards. Recently, antimicrobial peptides (AMPs) have been recognized as promising antiviral agents. Indeed, while the antibacterial and antifungal effects of these molecules have been widely reported, their use as potential antiviral agents has not yet been fully investigated. Herein, the antiviral activity of previously identified or newly designed AMPs was evaluated against the non-enveloped RNA viruses, hepatitis A virus (HAV) and murine norovirus (MNV), a surrogate for human norovirus. Moreover, specific assays were performed to recognize at which stage of the viral infection cycle the peptides could function. The results showed that almost all peptides displayed virucidal effects, with about 90% of infectivity reduction in HAV or MNV. However, the decapeptide RiLK1 demonstrated, together with its antibacterial and antifungal properties, a notable reduction in viral infection for both HAV and MNV, possibly through direct interaction with viral particles causing their damage or hindering the recognition of cellular receptors. Hence, RiLK1 could represent a versatile antimicrobial agent effective against various foodborne pathogens including viruses, bacteria, and fungi.

N-Heterocycles as Promising Antiviral Agents: A Comprehensive Overview.

Viruses are a real threat to every organism at any stage of life leading to extensive infections and casualties. N-heterocycles can affect the viral life cycle at many points, including viral entrance into host cells, viral genome replication, and the production of novel viral species. Certain N-heterocycles can also stimulate the host's immune system, producing antiviral cytokines and chemokines that can stop the reproduction of viruses. This review focused on recent five- or six-membered synthetic N-heterocyclic molecules showing antiviral activity through SAR analyses. The review will assist in identifying robust scaffolds that might be utilized to create effective antiviral drugs with either no or few side effects.

Assembly of Glycopeptides in Living Cells Resembling Viral Infection for Cargo Delivery.

Self-assembly in living cells represents one versatile strategy for drug delivery; however, it suffers from the limited precision and efficiency. Inspired by viral traits, we here report a cascade targeting-hydrolysis-transformation (THT) assembly of glycosylated peptides in living cells holistically resembling viral infection for efficient cargo delivery and combined tumor therapy. We design a glycosylated peptide via incorporating a ß-galactose-serine residue into bola-amphiphilic sequences. Co-assembling of the glycosylated peptide with two counterparts containing irinotecan (IRI) or ligand TSFAEYWNLLSP (PMI) results in formation of the glycosylated co-assemblies SgVEIP, which target cancer cells via ß-galactose-galectin-1 association and undergo galactosidase-induced morphological transformation. While GSH-reduction causes release of IRI from the co-assemblies, the PMI moieties release p53 and facilitate cell death via binding with protein MDM2. Cellular experiments show membrane targeting, endo-/lysosome-mediated internalization and in situ formation of nanofibers in cytoplasm by SgVEIP. This cascade THT process enables efficient delivery of IRI and PMI into cancer cells secreting Gal-1 and overexpressing ß-galactosidase. In vivo studies illustrate enhanced tumor accumulation and retention of the glycosylated co-assemblies, thereby suppressing tumor growth. Our findings demonstrate an in situ assembly strategy mimicking viral infection, thus providing a new route for drug delivery and cancer therapy in the future.

Antiviral Chemotherapy in Avian Medicine-A Review.

This review article describes the current knowledge about the use of antiviral chemotherapeutics in avian species, such as farm poultry and companion birds. Specific therapeutics are described in alphabetical order including classic antiviral drugs, such as acyclovir, abacavir, adefovir, amantadine, didanosine, entecavir, ganciclovir, interferon, lamivudine, penciclovir, famciclovir, oseltamivir, ribavirin, and zidovudine, repurposed drugs, such as ivermectin and nitazoxanide, which were originally used as antiparasitic drugs, and some others substances showing antiviral activity, such as ampligen, azo derivates, docosanol, fluoroarabinosylpyrimidine nucleosides, and novel peptides. Most of them have only been used for research purposes and are not widely used in clinical practice because of a lack of essential pharmacokinetic and safety data. Suggested future research directions are also highlighted.

T Cell and Natural Killer Cell Membrane-Camouflaged Nanoparticles for Cancer and Viral Therapies.

Extensive research has been conducted on the application of nanoparticles in the treatment of cancer and infectious diseases. Due to their exceptional characteristics and flexible structure, they are classified as highly efficient drug delivery systems, ensuring both safety and targeted delivery. Nevertheless, nanoparticles still encounter obstacles, such as biological instability, absence of selectivity, recognition as unfamiliar elements, and quick elimination, which restrict their remedial capacity. To surmount these drawbacks, biomimetic nanotechnology has been developed that utilizes T cell and natural killer (NK) cell membrane-encased nanoparticles as sophisticated methods of administering drugs. These nanoparticles can extend the duration of drug circulation and avoid immune system clearance. During the membrane extraction and coating procedure, the surface proteins of immunological cells are transferred to the biomimetic nanoparticles. Such proteins present on the surface of cells confer several benefits to nanoparticles, including prolonged circulation, enhanced targeting, controlled release, specific cellular contact, and reduced in vivo toxicity. This review focuses on biomimetic nanosystems that are derived from the membranes of T cells and NK cells and their comprehensive extraction procedure, manufacture, and applications in cancer treatment and viral infections. Furthermore, potential applications, prospects, and existing challenges in their medical implementation are highlighted.

Viral RNA capping: Mechanisms and antiviral therapy.

RNA capping is an essential trigger for protein translation in eukaryotic cells. Many viruses have evolved various strategies for initiating the translation of viral genes and generating progeny virions in infected cells via synthesizing cap structure or stealing the RNA cap from nascent host messenger ribonucleotide acid (mRNA). In addition to protein translation, a new understanding of the role of the RNA cap in antiviral innate immunity has advanced the field of mRNA synthesis in vitro and therapeutic applications. Recent studies on these viral RNA capping systems have revealed startlingly diverse ways and molecular machinery. A comprehensive understanding of how viruses accomplish the RNA capping in infected cells is pivotal for designing effective broad-spectrum antiviral therapies. Here we systematically review the contemporary insights into the RNA-capping mechanisms employed by viruses causing human and animal infectious diseases, while also highlighting its impact on host antiviral innate immune response. The therapeutic applications of targeting RNA capping against viral infections and the development of RNA-capping inhibitors are also summarized.

Microbial lectins as a potential therapeutics for the prevention of certain human diseases.

Lectins are protein or glycoprotein molecules with a specific ability to bind to carbohydrates. From viruses to mammals, they are found in various organisms and exhibit remarkable diverse structures and functions. They are significant contributors to defense mechanisms against microbial attacks in plants. They are also involved in functions such as controlling lymphocyte migration, regulating glycoprotein biosynthesis, cell-cell recognition, and embryonic development in animals. In addition, lectins serve as invaluable molecular tools in various biological and medical disciplines due to their reversible binding ability and enable the monitoring of cell membrane changes in physiological and pathological contexts. Microbial lectins, often referred to as adhesins, play an important role in microbial colonization, pathogenicity, and interactions among microorganisms. Viral lectins are located in the bilayered viral membrane, whereas bacterial lectins are found intracellularly and on the bacterial cell surface. Microfungal lectins are typically intracellular and have various functions in host-parasite interaction, and in fungal growth and morphogenesis. Although microbial lectin studies are less extensive than those of plants and animals, they provide insights into the infection mechanisms and potential interventions. Glycan specificity, essential functions in infectious diseases, and applications in the diagnosis and treatment of viral and bacterial infections are critical aspects of microbial lectin research. In this review, we will discuss the application and therapeutic potential of viral, bacterial and microfungal lectins.

Virus-Induced Epilepsy vs. Epilepsy Patients Acquiring Viral Infection: Unravelling the Complex Relationship for Precision Treatment.

The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain viruses can induce epilepsy by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, epilepsy patients may be more susceptible to viral infections due to factors, such as compromised immune systems, anticonvulsant drugs, or surgical interventions. Neuroinflammation, a common factor in both scenarios, exhibits onset, duration, intensity, and consequence variations. It can modulate epileptogenesis, increase seizure susceptibility, and impact anticonvulsant drug pharmacokinetics, immune system function, and brain physiology. Viral infections significantly impact the clinical management of epilepsy patients, necessitating a multidisciplinary approach encompassing diagnosis, prevention, and treatment of both conditions. We delved into the dual dynamics of viruses inducing epilepsy and epilepsy patients acquiring viruses, examining the unique features of each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms of epilepsy induction, emphasize neuroinflammation's impact, and analyze its effects on anticonvulsant drug pharmacokinetics. Conversely, in epilepsy patients acquiring viruses, we detail the acquired virus, its interaction with existing epilepsy, neuroinflammation effects, and changes in anticonvulsant drug pharmacokinetics. Understanding this interplay advances precision therapies for epilepsy during viral infections, providing mechanistic insights, identifying biomarkers and therapeutic targets, and supporting optimized dosing regimens. However, further studies are crucial to validate tools, discover new biomarkers and therapeutic targets, and evaluate targeted therapy safety and efficacy in diverse epilepsy and viral infection scenarios.

Clinical Effect Analysis of Different Doses of Creatine Phosphate Sodium Combined with Immunoglobulin in the Treatment of Pediatric Viral Myocarditis.

The purpose of this paper was to unravel the clinical effect analysis of different doses of creatine phosphate sodium (CPS) combined with immunoglobulin in the treatment of pediatric viral myocarditis (VMC). One hundred and twenty children with VMC were recruited and randomized into three groups (40 patients each). Group I received 1.0 g of CPS dissolved in 100 mL of 5% glucose injection intravenously 1 time/day; group II received 1.25 g of CPS dissolved in 125 mL of 5% glucose injection intravenously 1 time/day; group III received 1.5 g of CPS dissolved in 150 mL of 5% glucose injection intravenously 1 time/day; then all three groups were treated with combined use of immunoglobulin (300-400 mg/day) intravenously once a day; and all three groups were treated for 14 days. The clinical efficacy, cardiac function, serum inflammatory factor levels, immune function, and the occurrence of drug toxicity and adverse effects of the children in the three groups were compared after 14 days of treatment. All three groups achieved better therapeutic effects after treatment, in which the effective rate of the Group II and Group III was notably higher versus the Group I. Lower levels of cTnI, CK-MB, LDH, AST, IL-18, IL-6, IFN-γ, and LVEDD and higher CD3+, CD4+, and CD4+/CD8+, FS, and LVEF values were noted in the Group II and Group III versus the Group I, and the results were more pronounced in the high-dose group. The liver and kidney functions of the children in the three groups before and after treatment did not show any significant changes and the incidence of adverse reactions during the treatment period was low in all three groups. Children with VMC can be treated with high-dose CPS in combination with immunoglobulin, which can improve their cardiac function and immune function and reduce the inflammatory response with good overall therapeutic efficacy and fewer adverse effects.

A prospects tool in virus research: Analyzing the applications of organoids in virus studies.

Organoids have emerged as a powerful tool for understanding the biology of the respiratory, digestive, nervous as well as urinary system, investigating infections, and developing new therapies. This article reviews recent progress in the development of organoid and advancements in virus research. The potential applications of these models in studying virul infections, pathogenesis, and antiviral drug discovery are discussed.

IFNα Subtypes in HIV Infection and Immunity.

Type I interferons (IFN), immediately triggered following most viral infections, play a pivotal role in direct antiviral immunity and act as a bridge between innate and adaptive immune responses. However, numerous viruses have evolved evasion strategies against IFN responses, prompting the exploration of therapeutic alternatives for viral infections. Within the type I IFN family, 12 IFNα subtypes exist, all binding to the same receptor but displaying significant variations in their biological activities. Currently, clinical treatments for chronic virus infections predominantly rely on a single IFNα subtype (IFNα2a/b). However, the efficacy of this therapeutic treatment is relatively limited, particularly in the context of Human Immunodeficiency Virus (HIV) infection. Recent investigations have delved into alternative IFNα subtypes, identifying certain subtypes as highly potent, and their antiviral and immunomodulatory properties have been extensively characterized. This review consolidates recent findings on the roles of individual IFNα subtypes during HIV and Simian Immunodeficiency Virus (SIV) infections. It encompasses their induction in the context of HIV/SIV infection, their antiretroviral activity, and the diverse regulation of the immune response against HIV by distinct IFNα subtypes. These insights may pave the way for innovative strategies in HIV cure or functional cure studies.

Revolutionizing Antiviral Therapeutics: Unveiling Innovative Approaches for Enhanced Drug Efficacy.

Since the beginning of the coronavirus pandemic in late 2019, viral infections have become one of the top three causes of mortality worldwide. Immunization and the use of immunomodulatory drugs are effective ways to prevent and treat viral infections. However, the primary therapy for managing viral infections remains antiviral and antiretroviral medication. Unfortunately, these drugs are often limited by physicochemical constraints such as low target selectivity and poor aqueous solubility. Although several modifications have been made to enhance the physicochemical characteristics and efficacy of these drugs, there are few published studies that summarize and compare these modifications. Our review systematically synthesized and discussed antiviral drug modification reports from publications indexed in Scopus, PubMed, and Google Scholar databases. We examined various approaches that were investigated to address physicochemical issues and increase activity, including liposomes, cocrystals, solid dispersions, salt modifications, and nanoparticle drug delivery systems. We were impressed by how well each strategy addressed physicochemical issues and improved antiviral activity. In conclusion, these modifications represent a promising way to improve the physicochemical characteristics, functionality, and effectiveness of antivirals in clinical therapy.

Mitogen-activated protein kinase-guided drug discovery for post-viral and related types of lung disease.

Respiratory viral infections are a major public health problem, with much of their morbidity and mortality due to post-viral lung diseases that progress and persist after the active infection is cleared. This paradigm is implicated in the most common forms of chronic lung disease, such as asthma and COPD, as well as other virus-linked diseases including progressive and long-term coronavirus disease 2019. Despite the impact of these diseases, there is a lack of small-molecule drugs available that can precisely modify this type of disease process. Here we will review current progress in understanding the pathogenesis of post-viral and related lung disease with characteristic remodelling phenotypes. We will also develop how this data leads to mitogen-activated protein kinase (MAPK) in general and MAPK13 in particular as key druggable targets in this pathway. We will also explore recent advances and predict the future breakthroughs in structure-based drug design that will provide new MAPK inhibitors as drug candidates for clinical applications. Each of these developments point to a more effective approach to treating the distinct epithelial and immune cell based mechanisms, which better account for the morbidity and mortality of post-viral and related types of lung disease. This progress is vital given the growing prevalence of respiratory viruses and other inhaled agents that trigger stereotyped progression to acute illness and chronic disease.