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Immunocompromised people are at high risk of prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and progression to severe coronavirus disease 2019 (COVID-19). However, the efficacy of late-onset direct-acting antiviral (DAA) therapy with therapeutics in clinical use and experimental drugs to mitigate persistent viral replication is unclear. In this study, we employed an immunocompromised mouse model, which supports prolonged replication of SARS-CoV-2 to explore late-onset treatment options. Tandem immuno-depletion of CD4+ and CD8+ T cells in C57BL/6 mice followed by infection with SARS-CoV-2 variant of concern (VOC) beta B.1.351 resulted in prolonged infection with virus replication for 5 weeks after inoculation. Early-onset treatment with nirmatrelvir/ritonavir (paxlovid) or molnupiravir was only moderately efficacious, whereas the experimental therapeutic 4'-fluorouridine (4'-FlU, EIDD-2749) significantly reduced virus load in the upper and lower respiratory compartments 4 days postinfection (dpi). All antivirals significantly lowered virus burden in a 7-day treatment regimen initiated 14 dpi, but paxlovid-treated animals experienced rebound virus replication in the upper respiratory tract 7 days after treatment end. Viral RNA was detectable 28 dpi in paxlovid-treated animals, albeit not in the molnupiravir or 4'-FlU groups, when treatment was initiated 14 dpi and continued for 14 days. Low-level virus replication continued 35 dpi in animals receiving vehicle but had ceased in all treatment groups. These data indicate that late-onset DAA therapy significantly shortens the duration of persistent virus replication in an immunocompromised host, which may have implications for clinical use of antiviral therapeutics to alleviate the risk of progression to severe disease in highly vulnerable patients. IMPORTANCE: Four years after the onset of the global coronavirus disease 2019 (COVID-19) pandemic, the immunocompromised are at greatest risk of developing life-threatening severe disease. However, specific treatment plans for this most vulnerable patient group have not yet been developed. Employing a CD4+ and CD8+ T cell-depleted immunocompromised mouse model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we explored therapeutic options of persistent infections with standard-of-care paxlovid, molnupiravir, and the experimental therapeutic 4'-fluorouridine (4'-FlU). Late-onset treatment initiated 14 days after infection was efficacious, but only 4'-FlU was rapidly sterilizing. No treatment-experienced viral variants with reduced susceptibility to the drugs emerged, albeit virus replication rebounded in animals of the paxlovid group after treatment end. This study supports the use of direct-acting antivirals (DAAs) for late-onset management of persistent SARS-CoV-2 infection in immunocompromised hosts. However, treatment courses likely require to be extended for maximal therapeutic benefit, calling for appropriately powered clinical trials to meet the specific needs of this patient group.
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Neutralizing antibodies are important for immunity against SARS-CoV-2 and as therapeutics for the prevention and treatment of COVID-19. Here, we identified high-affinity nanobodies from alpacas immunized with coronavirus spike and receptor-binding domains (RBD) that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2. Epitope mapping, X-ray crystallography, and cryo-electron microscopy revealed two distinct antigenic sites and showed two neutralizing nanobodies from different epitope classes bound simultaneously to the spike trimer. Nanobody-Fc fusions of the four most potent nanobodies blocked ACE2 engagement with RBD variants present in human populations and potently neutralized both wild-type SARS-CoV-2 and the N501Y D614G variant at concentrations as low as 0.1 nM. Prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 104-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , SARS-CoV-2/imunologia , Anticorpos de Domínio Único , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/farmacologia , COVID-19/imunologia , Camelídeos Americanos , Humanos , Camundongos , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/farmacologiaRESUMO
An essential mechanism for severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection begins with the viral spike protein binding to the human receptor protein angiotensin-converting enzyme II (ACE2). Here, we describe a stepwise engineering approach to generate a set of affinity optimized, enzymatically inactivated ACE2 variants that potently block SARS-CoV-2 infection of cells. These optimized receptor traps tightly bind the receptor binding domain (RBD) of the viral spike protein and prevent entry into host cells. We first computationally designed the ACE2-RBD interface using a two-stage flexible protein backbone design process that improved affinity for the RBD by up to 12-fold. These designed receptor variants were affinity matured an additional 14-fold by random mutagenesis and selection using yeast surface display. The highest-affinity variant contained seven amino acid changes and bound to the RBD 170-fold more tightly than wild-type ACE2. With the addition of the natural ACE2 collectrin domain and fusion to a human immunoglobulin crystallizable fragment (Fc) domain for increased stabilization and avidity, the most optimal ACE2 receptor traps neutralized SARS-CoV-2-pseudotyped lentivirus and authentic SARS-CoV-2 virus with half-maximal inhibitory concentrations (IC50s) in the 10- to 100-ng/mL range. Engineered ACE2 receptor traps offer a promising route to fighting infections by SARS-CoV-2 and other ACE2-using coronaviruses, with the key advantage that viral resistance would also likely impair viral entry. Moreover, such traps can be predesigned for viruses with known entry receptors for faster therapeutic response without the need for neutralizing antibodies isolated from convalescent patients.
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Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/química , Desenho de Fármacos , Engenharia de Proteínas/métodos , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/genética , Antivirais/metabolismo , Sítios de Ligação , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , Mutação , Biblioteca de Peptídeos , Ligação Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae , Glicoproteína da Espícula de Coronavírus/químicaRESUMO
INTRODUCTION: Coronavirus disease 2019 (COVID-19) is an illness caused by the new coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). It has affected public health and the economy globally. Currently approved vaccines and other drug candidates could be associated with several drawbacks which urges developing alternative therapeutic approaches. AIM: To provide a comprehensive review of anti-SARS-CoV-2 activities of plants and their bioactive compounds. METHODS: Information was gathered from diverse bibliographic platforms such as PubMed, Google Scholar, and ClinicalTrials.gov registry. RESULTS: The present review highlights the potential roles of crude extracts of plants as well as plant-derived small molecules in inhibiting SARS-CoV-2 infection by targeting viral or host factors essential for viral entry, polyprotein processing, replication, assembly and release. Their anti-inflammatory and antioxidant properties as well as plant-based therapies that are under development in the clinical trial phases-1 to 3 are also covered. CONCLUSION: This knowledge could further help understanding SARS-CoV-2 infection and anti-viral mechanisms of plant-based therapeutics.
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Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Internalização do VírusRESUMO
The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.
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Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , COVID-19/virologia , Desenvolvimento de Medicamentos , Humanos , National Institutes of Health (U.S.) , Peptídeo Hidrolases/metabolismo , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Estados Unidos , Replicação Viral/efeitos dos fármacosRESUMO
Nanotechnology can offer a number of options against coronavirus disease 2019 (COVID-19) acting both extracellularly and intracellularly to the host cells. Here, the aim is to explore graphene oxide (GO), the most studied 2D nanomaterial in biomedical applications, as a nanoscale platform for interaction with SARS-CoV-2. Molecular docking analyses of GO sheets on interaction with three different structures: SARS-CoV-2 viral spike (open state - 6VYB or closed state - 6VXX), ACE2 (1R42), and the ACE2-bound spike complex (6M0J) are performed. GO shows high affinity for the surface of all three structures (6M0J, 6VYB and 6VXX). When binding affinities and involved bonding types are compared, GO interacts more strongly with the spike or ACE2, compared to 6M0J. Infection experiments using infectious viral particles from four different clades as classified by Global Initiative on Sharing all Influenza Data (GISAID), are performed for validation purposes. Thin, biological-grade GO nanoscale (few hundred nanometers in lateral dimension) sheets are able to significantly reduce copies for three different viral clades. This data has demonstrated that GO sheets have the capacity to interact with SARS-CoV-2 surface components and disrupt infectivity even in the presence of any mutations on the viral spike. GO nanosheets are proposed to be further explored as a nanoscale platform for development of antiviral strategies against COVID-19.
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COVID-19 , Glicoproteína da Espícula de Coronavírus , Grafite , Humanos , Proteínas de Membrana , Simulação de Acoplamento Molecular , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China at the end of 2019 and has rapidly caused a pandemic, with over 20 million recorded COVID-19 cases in August 2020 (https://covid19.who.int/). There are no FDA-approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA-approved drugs. Rapid development and human testing of potential antivirals is urgently needed. Numerous drugs are already approved for human use, and subsequently, there is a good understanding of their safety profiles and potential side effects, making them easier to fast-track to clinical studies in COVID-19 patients. Here, we present data on the antiviral activity of 20 FDA-approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that 17 of these inhibit SARS-CoV-2 at non-cytotoxic concentrations. We directly followed up seven of these to demonstrate that all are capable of inhibiting infectious SARS-CoV-2 production. Moreover, we evaluated two of these, chloroquine and chlorpromazine, in vivo using a mouse-adapted SARS-CoV model and found that both drugs protect mice from clinical disease.IMPORTANCE There are no FDA-approved antivirals for any coronavirus, including SARS-CoV-2. Numerous drugs are already approved for human use that may have antiviral activity and therefore could potentially be rapidly repurposed as antivirals. Here, we present data assessing the antiviral activity of 20 FDA-approved drugs against SARS-CoV-2 that also inhibit SARS-CoV and MERS-CoV in vitro We found that 17 of these inhibit SARS-CoV-2, suggesting that they may have pan-anti-coronaviral activity. We directly followed up seven of these and found that they all inhibit infectious-SARS-CoV-2 production. Moreover, we evaluated chloroquine and chlorpromazine in vivo using mouse-adapted SARS-CoV. We found that neither drug inhibited viral replication in the lungs, but both protected against clinical disease.
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Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Células A549 , Animais , COVID-19 , Cloroquina/farmacologia , Clorpromazina/farmacologia , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Pandemias , SARS-CoV-2 , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Replicação Viral/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Although great advances have been made on large-scale manufacturing of vaccines and antiviral-based drugs, viruses persist as the major cause of human diseases nowadays. The recent pandemic of coronavirus disease-2019 (COVID-19) mounts a lot of stress on the healthcare sector and the scientific society to search continuously for novel components with antiviral possibility. Herein, we narrated the different tactics of using biopeptides as antiviral molecules that could be used as an interesting alternative to treat COVID-19 patients. The number of peptides with antiviral effects is still low, but such peptides already displayed huge potentials to become pharmaceutically obtainable as antiviral medications. Studies showed that animal venoms, mammals, plant, and artificial sources are the main sources of antiviral peptides, when bioinformatics tools are used. This review spotlights bioactive peptides with antiviral activities against human viruses, especially the coronaviruses such as severe acute respiratory syndrome (SARS) virus, Middle East respiratory syndrome (MERS) virus, and severe acute respiratory syndrome coronavirus 2 (SARS-COV-2 or SARS-nCOV19). We also showed the data about well-recognized peptides that are still under investigations, while presenting the most potent ones that may become medications for clinical use.
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Antivirais , COVID-19 , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Peptídeos , Estudos Prospectivos , SARS-CoV-2RESUMO
Posttranslational modifications of targeted substrates alter their cellular fate. Ubiquitin is a highly conserved and ubiquitous covalent modifier protein that tags substrates with a single molecule or with a polyubiquitin chain. Monoubiquitination affects trafficking and signaling patterns of modified proteins. In contrast, polyubiquitination, particularly K48-linked polyubiquitination, targets the protein for degradation by the Ubiquitin-Proteasome System (UPS) resulting in a committed fate through irreversible inactivation of substrate. Given the diversity of cellular functions impacted by ubiquitination, it is no surprise that the wily pathogenic viruses have co-opted the UPS in myriad ways to ensure their survival. In this review, I describe viral exploitation of nondegradative ubiquitin signaling pathways to effect entry, replication, and egress. Additionally, viruses also harness the UPS to degrade antiviral cellular host factors. Finally, I describe how we can exploit the same proteolytic machinery to enable PROTACs (Proteolysis-Targeting Chimeras) to degrade essential viral proteins. Successful implementation of this modality will add to the arsenal of emerging antiviral therapies.
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Antivirais , Ubiquitina , Antivirais/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
DiNap [(E)-1-(2-hydroxy-4,6-dimethoxyphenyl)-3-(naphthalen-1-yl)prop-2-en-1-one], an analog of a natural product (the chalcone flavokawain), was synthesized and characterized in this study. Porcine reproductive and respiratory syndrome virus (PRRSV) is the most challenging threat to the swine industry worldwide. Currently, commercially available vaccines are ineffective for controlling porcine reproductive and respiratory syndrome (PRRS) in pigs. Therefore, a pharmacological intervention may represent an alternative control measure for PRRSV infection. Hence, the present study evaluated the effects of DiNap on the replication of VR2332 (a prototype strain of type 2 PRRSV). Initially, in vitro antiviral assays against VR2332 were performed in MARC-145 cells and porcine alveolar macrophages (PAMs). Following this, a pilot study was conducted in a pig model to demonstrate the effects of DiNap following VR2332 infection. DiNap inhibited VR2332 replication in both cell lines in a dose-dependent manner, and viral growth was completely suppressed at concentrations ≥0.06 mM, without significant cytotoxicity. Consistent with these findings, in the pig study, DiNap also reduced viral loads in the serum and lungs and enhanced the weight gain of pigs following VR2332 infection, as indicated by comparison of the DiNap-treated groups to the untreated control (NC) group. In addition, DiNap-treated pigs had fewer gross and microscopic lesions in their lungs than NC pigs. Notably, virus transmission was also delayed by approximately 1 week in uninfected contact pigs within the same group after treatment with DiNap. Taken together, these results suggest that DiNap has potential anti-PRRSV activity and could be useful as a prophylactic or post-exposure treatment drug to control PRRSV infection in pigs.
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Produtos Biológicos/química , Flavonoides/química , Síndrome Respiratória e Reprodutiva Suína/tratamento farmacológico , Replicação Viral/efeitos dos fármacos , Animais , Produtos Biológicos/administração & dosagem , Produtos Biológicos/síntese química , Chalcona/administração & dosagem , Chalcona/síntese química , Chalcona/química , Flavonoides/administração & dosagem , Flavonoides/síntese química , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Macrófagos Alveolares/efeitos dos fármacos , Projetos Piloto , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína , Suínos/virologia , Carga ViralRESUMO
Dengue is an important global threat caused by dengue virus (DENV) that records an estimated 390 million infections annually. Despite the availability of CYD-TDV as a commercial vaccine, its long-term efficacy against all four dengue virus serotypes remains unsatisfactory. There is therefore an urgent need for the development of antiviral drugs for the treatment of dengue. Peptide was once a neglected choice of medical treatment but it has lately regained interest from the pharmaceutical industry following pioneering advancements in technology. In this review, the design of peptide drugs, antiviral activities and mechanisms of peptides and peptidomimetics (modified peptides) action against dengue virus are discussed. The development of peptides as inhibitors for viral entry, replication and translation is also described, with a focus on the three main targets, namely, the host cell receptors, viral structural proteins and viral non-structural proteins. The antiviral peptides designed based on these approaches may lead to the discovery of novel anti-DENV therapeutics that can treat dengue patients.
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Vírus da Dengue/efeitos dos fármacos , Dengue/tratamento farmacológico , Peptídeos/uso terapêutico , Peptidomiméticos/uso terapêutico , Antivirais/uso terapêutico , Dengue/epidemiologia , Dengue/virologia , Vacinas contra Dengue/uso terapêutico , Vírus da Dengue/patogenicidade , Humanos , Internalização do Vírus/efeitos dos fármacosRESUMO
African swine fever (ASF) causes high mortality in pigs and threatens global swine production. There is still a lack of therapeutics available, with two vaccines under scrutiny and no approved small-molecule drugs. Eleven (11) viral proteins were used to identify potential antivirals in in silico screening of secondary metabolites (127) from Chlorella spp. The metabolites were screened for affinity and binding selectivity. High-scoring compounds were assessed through in silico ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) predictions, compared to structurally similar drugs, and checked for off-target docking with prepared swine receptors. Molecular dynamics (MD) simulations determined binding stability while binding energy was measured in Molecular Mechanics - Generalized Born Surface Area (MMGBSA) or Poisson-Boltzmann Surface Area (MMPBSA). Only six (6) compounds passed until MD analyses, of which five (5) were stable after 100 ns of MD runs. Of these five compounds, only three had binding affinities that were comparable to or stronger than controls. Specifically, phytosterols 24,25-dihydrolanosterol and CID 4206521 that interact with the RNA capping enzyme (pNP868R), and ergosterol which bound to the Erv-like thioreductase (pB119L). The compounds identified in this study can be used as a theoretical basis for in vitro screening to develop potent antiviral drugs against ASFV.
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We present a bioprinted three-layered airway model with a physiologically relevant microstructure for the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dynamics. This model exhibited clear cell-cell junctions and mucus secretion with an efficient expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Having infected air-exposed epithelial cells in the upper layer with a minimum multiplicity of infection of 0.01, the airway model showed a marked susceptibility to SARS-CoV-2 within one-day post-infection (dpi). Furthermore, the unique longevity allowed the observation of cytopathic effects and barrier degradation for 21 dpi. The in-depth transcriptomic analysis revealed dramatic changes in gene expression affecting the infection pathway, viral proliferation, and host immune response which are consistent with COVID-19 patient data. Finally, the treatment of antiviral agents, such as remdesivir and molnupiravir, through the culture medium underlying the endothelium resulted in a marked inhibition of viral replication within the epithelium. The bioprinted airway model can be used as a manufacturable physiological platform to study disease pathogeneses and drug efficacy.
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Enzima de Conversão de Angiotensina 2 , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Impressão Tridimensional , SARS-CoV-2 , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/virologia , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Bioimpressão/métodos , Células Epiteliais/virologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Serina Endopeptidases/metabolismo , Alanina/análogos & derivadosRESUMO
Simplexvirus humanalpha1 (Herpes simplex virus type 1 [HSV-1]) infects millions of people globally, manifesting as vesiculo-ulcerative lesions of the oral or genital mucosa. After primary infection, the virus establishes latency in the peripheral neurons and reactivates sporadically in response to various environmental and genetic factors. A unique feature of herpesviruses is their ability to encode tiny noncoding RNAs called microRNA (miRNAs). Simplexvirus humanalpha1 encodes eighteen miRNA precursors that generate twentyseven different mature miRNA sequences. Unique Simplexvirus humanalpha1 miRNAs repertoire is expressed in lytic and latent stages and exhibits expressional disparity in various cell types and model systems, suggesting their key pathological functions. This review will focus on elucidating the mechanisms underlying the regulation of host-virus interaction by HSV-1 encoded viral miRNAs. Numerous studies have demonstrated sequence- specific targeting of both viral and host transcripts by Simplexvirus humanalpha1 miRNAs. While these noncoding RNAs predominantly target viral genes involved in viral life cycle switch, they regulate host genes involved in antiviral immunity, thereby facilitating viral evasion and lifelong viral persistence inside the host. Expression of Simplexvirus humanalpha1 miRNAs has been associated with disease progression and resolution. Systemic circulation and stability of viral miRNAs compared to viral mRNAs can be harnessed to utilize their potential as diagnostic and prognostic markers. Moreover, functional inhibition of these enigmatic molecules may allow us to devise strategies that have therapeutic significance to contain Simplexvirus humanalpha1 infection.
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Herpesvirus Humano 1 , MicroRNAs , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Herpesvirus Humano 1/genética , RNA Viral/genética , Herpes Simples/virologia , Herpes Simples/genética , AnimaisRESUMO
We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.
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Antivirais , Antivirais/farmacologia , Antivirais/química , Humanos , Animais , Proteínas 14-3-3/metabolismo , Complexos Multiproteicos/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Linhagem CelularRESUMO
Equid alphaherpesvirus type 8 (EqHV-8) is the causative agent of severe respiratory disease, abortions, and neurological syndromes in equines and has resulted in huge economic losses to the donkey industry. Currently, there exist no therapeutic molecules for controlling EqHV-8 infection. We evaluated the potential antiviral activity of cobalt protoporphyrin (CoPP) against EqHV-8 infection. Our results demonstrated that CoPP inhibited EqHV-8 infection in susceptible cells and mouse models. Furthermore, CoPP blocked the replication of EqHV-8 via HO-1 (heme oxygenase-1) mediated type I interferon (IFN) response. In conclusion, our data suggested that CoPP could serve as a novel potential molecule to develop an effective therapeutic strategy for EqHV-8 prevention and control.
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Neuroendocrine neoplasms (NENs) comprise malignancies involving neuroendocrine cells that often lead to fatal pathological conditions. Despite escalating global incidences, NENs still have poor prognoses. Interestingly, research indicates an intricate association of tumor viruses with NENs. However, there is a dearth of comprehension of the complete scenario of NEN pathophysiology and its precise connections with the tumor viruses. Interestingly, several cutting-edge experiments became helpful for further screening of NET for the presence of polyomavirus, Human papillomavirus (HPV), Kaposi sarcoma-associated herpesvirus (KSHV), Epstein Barr virus (EBV), etc. Current research on the neuroendocrine tumor (NET) pathogenesis provides new information concerning their molecular mechanisms and therapeutic interventions. Of note, scientists observed that metastatic neuroendocrine tumors still have a poor prognosis with a palliative situation. Different oncolytic vector has already demonstrated excellent efficacies in clinical studies. Therefore, oncolytic virotherapy or virus-based immunotherapy could be an emerging and novel therapeutic intervention. In-depth understanding of all such various aspects will aid in managing, developing early detection assays, and establishing targeted therapeutic interventions for NENs concerning tumor viruses. Hence, this review takes a novel approach to discuss the dual role of tumor viruses in association with NENs' pathophysiology as well as its potential therapeutic interventions.
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Carcinoma Neuroendócrino , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 8 , Tumores Neuroendócrinos , Humanos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4 , Tumores Neuroendócrinos/terapia , Tumores Neuroendócrinos/patologiaRESUMO
Timely intervention of preventative and therapeutic measures abated a 2022 mpox global outbreak. However, the high transmissibility and unique pathological characteristics of mpox demand further investigation. Here, we discuss the potentials of human skin-on-a-chip as a valuable model for mpox disease evaluation, to achieve in-depth physiological understanding and desirable therapeutic predictive capabilities.
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Mpox , Humanos , Avaliação Pré-Clínica de Medicamentos , Dispositivos Lab-On-A-ChipRESUMO
RNA viruses always have been a serious concern for human health by causing several outbreaks, often pandemics. The excessive mortality and deaths associated with the outbreaks caused by these viruses were due to the excessive induction of pro-inflammatory cytokines leading to cytokine storm. Cytokines are important for cell-to-cell communication to maintain cell homeostasis. Disturbances of this homeostasis can lead to intricate chain reactions resulting in a massive release of cytokines. This could lead to a severe self-reinforcement of several feedback processes, which could eventually cause systemic harm, multiple organ failure, or death. Multiple inflammation-associated pathways were involved in the cytokine production and its regulation. Different RNA viruses induce these pathways through the interplay with their viral factors and host proteins and miRNAs regulating these pathways. This review will discuss the interplay of host proteins and miRNAs that can play an important role in the regulation of cytokine storm and the possible therapeutic potential of these molecules for the treatment and the challenges associated with the clinical translation.
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Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 ligase ligand, recruit a target protein to the E3 ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique viral proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals.