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Viruses May 2024Despite their small and simple structure compared with their hosts, virus particles can cause severe harm and even mortality in highly evolved species such as humans. A...
Despite their small and simple structure compared with their hosts, virus particles can cause severe harm and even mortality in highly evolved species such as humans. A comprehensive quantitative biophysical understanding of intracellular virus replication mechanisms could aid in preparing for future virus pandemics. By elucidating the relationship between the form and function of intracellular structures from the host cell and viral components, it is possible to identify possible targets for direct antiviral agents and potent vaccines. Biophysical investigations into the spatio-temporal dynamics of intracellular virus replication have thus far been limited. This study introduces a framework to enable simulations of these dynamics using partial differential equation (PDE) models, which are evaluated using advanced numerical mathematical methods on leading supercomputers. In particular, this study presents a model of the replication cycle of a specific RNA virus, the hepatitis C virus. The diffusion-reaction model mimics the interplay of the major components of the viral replication cycle, including non structural viral proteins, viral genomic RNA, and a generic host factor. Technically, surface partial differential equations (sufPDEs) are coupled on the 3D embedded 2D endoplasmic reticulum manifold with partial differential equations (PDEs) in the 3D membranous web and cytosol volume. The membranous web serves as a viral replication factory and is formed on the endoplasmic reticulum after infection and in the presence of nonstructural proteins. The coupled sufPDE/PDE model was evaluated using realistic cell geometries based on experimental data. The simulations incorporate the effects of non structural viral proteins, which are restricted to the endoplasmic reticulum surface, with effects appearing in the volume, such as host factor supply from the cytosol and membranous web dynamics. Because the spatial diffusion properties of genomic viral RNA are not yet fully understood, the model allows for viral RNA movement on the endoplasmic reticulum as well as within the cytosol. Visualizing the simulated intracellular viral replication dynamics provides insights similar to those obtained by microscopy, complementing data from in vitro/in vivo viral replication experiments. The output data demonstrate quantitative consistence with the experimental findings, prompting further advanced experimental studies to validate the model and refine our quantitative biophysical understanding.
Topics: Virus Replication; Humans; Computer Simulation; Hepacivirus; Endoplasmic Reticulum; RNA, Viral; Models, Biological; Spatio-Temporal Analysis
PubMed: 38932132
DOI: 10.3390/v16060840 -
Viruses May 2024The COVID-19 pandemic has been one of the most impactful events in our lifetime, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple... (Review)
Review
The COVID-19 pandemic has been one of the most impactful events in our lifetime, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Multiple SARS-CoV-2 variants were reported globally, and a wide range of symptoms existed. Individuals who contract COVID-19 continue to suffer for a long time, known as long COVID or post-acute sequelae of COVID-19 (PASC). While COVID-19 vaccines were widely deployed, both unvaccinated and vaccinated individuals experienced long-term complications. To date, there are no treatments to eradicate long COVID. We recently conceived a new approach to treat COVID in which a 15-amino-acid synthetic peptide (SPIKENET, SPK) is targeted to the ACE2 receptor binding domain of SARS-CoV-2, which prevents the virus from attaching to the host. We also found that SPK precludes the binding of spike glycoproteins with the receptor carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) of a coronavirus, murine hepatitis virus-1 (MHV-1), and with all SARS-CoV-2 variants. Further, SPK reversed the development of severe inflammation, oxidative stress, tissue edema, and animal death post-MHV-1 infection in mice. SPK also protects against multiple organ damage in acute and long-term post-MHV-1 infection. Our findings collectively suggest a potential therapeutic benefit of SPK for treating COVID-19.
Topics: SARS-CoV-2; Humans; COVID-19; Animals; Spike Glycoprotein, Coronavirus; Mice; Post-Acute COVID-19 Syndrome; Angiotensin-Converting Enzyme 2; Peptides; Antiviral Agents; COVID-19 Drug Treatment
PubMed: 38932130
DOI: 10.3390/v16060838 -
Viruses May 2024Cytokinins (CKs) are a group of N-substituted signaling molecules whose biosynthesis and metabolism have been documented in all kingdoms of life, including vertebrates....
Cytokinins (CKs) are a group of N-substituted signaling molecules whose biosynthesis and metabolism have been documented in all kingdoms of life, including vertebrates. While their biological relevance in vertebrate systems continues to be elucidated, they have broadly been documented with therapeutic effects in exogenous applications. In this study, we evaluated the virostatic potential of four types of CKs including, -isopentenyladenine (iP), -isopentenyladenosine (iPR), -isopentenyladenosine-5'monophosphate (iPMP), and 2-methylthiol--isopentenyladenosine (2MeSiPR) against the ranavirus type species, frog virus 3 (FV3). Following concurrent treatment and infection, iP and iPR reduced viral replication by 33.8% and 59.6%, respectively, in plaque formation assays. A decrease in viral replication was also observed when CK exposure was limited to 12 h prior to infection, where iP and iPR reduced viral replication by 31% and 23.75%, respectively. Treatment with iP and iPR was also marked by 48% and 60% decreases in viral load over 72 h, respectively, as measured in single step growth curves. Plaque morphology was altered in vitro, as iP and iPR treatment increased plaque area by 83% and 112% with lytic zone formation also becoming more prevalent in corresponding treatments. Treatment with iPMP and 2MeSiPR resulted in no effect on viral kinetics in vitro. The results of this study are the first to provide evidence of CK antiviral activity against a DNA virus and highlight the importance of their structure for therapeutic investigations.
Topics: Virus Replication; Animals; Antiviral Agents; Ranavirus; Viral Plaque Assay; Cytokinins; Cell Line
PubMed: 38932119
DOI: 10.3390/v16060826 -
Viruses May 2024HIV-associated neurocognitive disorders (HAND) are highly prevalent in those ageing with HIV. High-income country data suggest that vascular risk factors (VRFs) may be...
HIV-associated neurocognitive disorders (HAND) are highly prevalent in those ageing with HIV. High-income country data suggest that vascular risk factors (VRFs) may be stronger predictors of HAND than HIV-disease severity, but data from sub-Saharan Africa are lacking. We evaluated relationships of VRFs, vascular end-organ damage and HAND in individuals aged ≥ 50 in Tanzania. c-ART-treated individuals were assessed for HAND using consensus criteria. The prevalence of VRFs and end organ damage markers were measured. The independent associations of VRFs, end organ damage and HAND were examined using multivariable logistic regression. Data were available for 153 individuals (median age 56, 67.3% female). HAND was highly prevalent (66.7%, 25.5% symptomatic) despite well-managed HIV (70.5% virally suppressed). Vascular risk factors included hypertension (34%), obesity (10.5%), hypercholesterolemia (33.3%), diabetes (5.3%) and current smoking (4.6%). End organ damage prevalence ranged from 1.3% (prior myocardial infarction) to 12.5% (left ventricular hypertrophy). Measured VRFs and end organ damage were not independently associated with HAND. The only significant association was lower diastolic BP ( 0.030, OR 0.969 (0.943-0.997). Our results suggest that vascular risk factors are not major drivers of HAND in this setting. Further studies should explore alternative aetiologies such as chronic inflammation.
Topics: Humans; Female; Male; Tanzania; Middle Aged; Risk Factors; HIV Infections; Aged; Prevalence; AIDS Dementia Complex; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Neurocognitive Disorders
PubMed: 38932112
DOI: 10.3390/v16060819 -
Pharmaceuticals (Basel, Switzerland) Jun 2024The open-source drug library, namely, MMV Pandemic Response Box, contains 153 antiviral agents, a chemically and pharmacologically diverse mixture of early-stage,...
The open-source drug library, namely, MMV Pandemic Response Box, contains 153 antiviral agents, a chemically and pharmacologically diverse mixture of early-stage, emerging anti-infective scaffolds, and mature compounds currently undergoing clinical development. Hence, the Pandemic Response Box might contain compounds that bind and interfere with target molecules or cellular pathways that are conserved or shared among the closely related viruses with enterovirus A71 (EV-A71). This study aimed to screen antiviral agents included in the Pandemic Response Box for repurposing to anti-EV-A71 activity and investigate the inhibitory effects of the compounds on viral replication. The compounds' cytotoxicity and ability to rescue infected cells were determined by % cell survival using an SRB assay. The hit compounds were verified for anti-EV-A71 activity by virus reduction assays for viral RNA copy numbers, viral protein synthesis, and mature particle production using qRT-PCR, Western blot analysis, and CCID assay, respectively. It was found that some of the hit compounds could reduce EV-A71 genome replication and protein synthesis. D-D7 (2-pyridone-containing human rhinovirus 3C protease inhibitor) exhibited the highest anti-EV-A71 activity. Even though D-D7 has been originally indicated as a polyprotein processing inhibitor of human rhinovirus 3C protease, it could be repurposed as an anti-EV-A71 agent.
PubMed: 38931452
DOI: 10.3390/ph17060785 -
Pharmaceuticals (Basel, Switzerland) May 2024Microbicides, which are classified as topical antiseptic agents, are a revolutionary advancement in HIV prevention aimed to prevent the entry of infectious agents into... (Review)
Review
Microbicides, which are classified as topical antiseptic agents, are a revolutionary advancement in HIV prevention aimed to prevent the entry of infectious agents into the human body, thus stopping the sexual transmission of HIV and other sexually transmitted diseases. Microbicides represent the promise of a new age in preventive measures against one of the world's most pressing health challenges. In addition to their direct antiviral effects during HIV transmission, microbicides also influence vaginal mucosal immunity. This article reviews microbicides by presenting different drug classifications and highlighting significant representatives from each group. It also explains their mechanisms of action and presents information about vaginal mucosal immune responses, emphasizing the critical role they play in responding to HIV during sexual transmission. The article discusses the following groups of microbicides: surfactants or membrane disruptors, vaginal milieu protectors, anionic polymers, dendrimers, carbohydrate-binding proteins, HIV replication inhibitors (reverse transcriptase inhibitors), and multi-purpose prevention technologies, which combine protection against HIV, other sexually transmitted diseases, and contraception. For each chemical compound, the article provides a brief overview of relevant preclinical and clinical research, emphasizing their potential as microbicides. The article offers insights into the multifaceted impact of microbicides, which signify a pivotal step forward in the pursuit of effective and accessible pre-exposure prophylaxis (PrEP).
PubMed: 38931337
DOI: 10.3390/ph17060668 -
Nutrients Jun 2024The immune system is affected by the dietary products humans intake. Immune system regulation by nutrition has uses in the clinical context, but it can also benefit... (Randomized Controlled Trial)
Randomized Controlled Trial
Prospective, Randomized, Double-Blind Parallel Group Nutritional Study to Evaluate the Effects of Routine Intake of Fresh vs. Pasteurized Yogurt on the Immune System in Healthy Adults.
The immune system is affected by the dietary products humans intake. Immune system regulation by nutrition has uses in the clinical context, but it can also benefit healthy populations by delaying or preventing the emergence of immune-mediated chronic illnesses. In this study, the purpose was to describe and compare the modulator effects on the immune system of the routine ingestion of fresh vs. pasteurized yogurt. A unicentral, prospective, randomized, double-blind, parallel group 8-week nutritional study was carried out comparing the ingestion of 125 g of the products in healthy adults three times a day. A complete battery of in vitro tests on the activity of the immune system, processes and phenomena was performed. Exclusive immune-modulatory effects of fresh yogurt with respect to base line were found in terms of increased systemic IgM (primary immune responses), increased synthesis of IFN-gamma upon stimulation (Th1) and increased peripheral T cells (mainly "naive" CD4s). In the three interventions, we observed an increased phagocytic activity and burst test in granulocytes, together with increased secretion of IL-6, IL-1 β and IL-8 (pro-inflammatory) and increased CD16 expression (FcR favoring phagocytosis) in granulocytes. Overall, it is concluded that regardless of bacteria being alive or thermally inactivated, yogurt has common effects on the innate system, but the presence of live bacteria is necessary to achieve a potentiating effect on the specific immune response.
Topics: Yogurt; Humans; Double-Blind Method; Adult; Male; Female; Prospective Studies; Pasteurization; Phagocytosis; Cytokines; Young Adult; Immunoglobulin M; Interferon-gamma; Middle Aged; Granulocytes; Immune System; Receptors, IgG
PubMed: 38931322
DOI: 10.3390/nu16121969 -
Nutrients Jun 2024Adenovirus (HAdV) can cause severe respiratory infections in children and immunocompromised patients. There is a lack of specific therapeutic drugs for HAdV infection,...
Adenovirus (HAdV) can cause severe respiratory infections in children and immunocompromised patients. There is a lack of specific therapeutic drugs for HAdV infection, and the study of anti-adenoviral drugs has far-reaching clinical implications. Elemental selenium can play a specific role as an antioxidant in the human immune cycle by non-specifically binding to the amino acid methionine in body proteins. Methods: The antiviral mechanism of selenomethionine was explored by measuring cell membrane status, intracellular DNA status, cytokine secretion, mitochondrial membrane potential, and ROS production. Conclusions: Selenomethionine improved the regulation of ROS-mediated apoptosis by modulating the expression of Jak1/2, STAT3, and BCL-XL, which led to the inhibition of apoptosis. It is anticipated that selenomethionine will offer a new anti-adenoviral therapeutic alternative.
Topics: Humans; Selenomethionine; Apoptosis; Signal Transduction; Reactive Oxygen Species; STAT3 Transcription Factor; Janus Kinases; Antiviral Agents; Membrane Potential, Mitochondrial; A549 Cells
PubMed: 38931321
DOI: 10.3390/nu16121966 -
Nutrients Jun 2024Saikosaponin D (SSD), derived from L., has various pharmacological properties, including immunoregulatory, anti-inflammatory, and anti-allergic effects. Several studies...
Saikosaponin D (SSD), derived from L., has various pharmacological properties, including immunoregulatory, anti-inflammatory, and anti-allergic effects. Several studies have investigated the anti-tumor effects of SSD on cancer in multiple organs. However, its role in colorectal cancer (CRC) remains unclear. Therefore, this study aimed to elucidate the suppressive effects of SSD on CRC cell survival and metastasis. SSD reduced the survival and colony formation ability of CRC cells. SSD-induced autophagy and apoptosis in CRC cells were measured using flow cytometry. SSD treatment increased LC3B and p62 autophagic factor levels in CRC cells. Moreover, SSD-induced apoptosis occurred through the cleavage of caspase-9, caspase-3, and PARP, along with the downregulation of the Bcl-2 family. In the in vivo experiment, a reduction in the number of metastatic tumor nodules in the lungs was observed after the oral administration of SSD. Based on these results, SSD inhibits the metastasis of CRC cells to the lungs by inducing autophagy and apoptosis. In conclusion, SSD suppressed the proliferation and metastasis of CRC cells, suggesting its potential as a novel substance for the metastatic CRC treatment.
Topics: Saponins; Oleanolic Acid; Autophagy; Colorectal Neoplasms; Apoptosis; Humans; Lung Neoplasms; Animals; Cell Line, Tumor; Cell Proliferation; Mice; Mice, Inbred BALB C; Antineoplastic Agents, Phytogenic; Xenograft Model Antitumor Assays; Cell Survival; Mice, Nude
PubMed: 38931199
DOI: 10.3390/nu16121844 -
Molecules (Basel, Switzerland) Jun 2024Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome...
Hepatitis B virus (HBV) remains a global health threat. Ribonuclease H (RNase H), part of the virus polymerase protein, cleaves the pgRNA template during viral genome replication. Inhibition of RNase H activity prevents (+) DNA strand synthesis and results in the accumulation of non-functional genomes, terminating the viral replication cycle. RNase H, though promising, remains an under-explored drug target against HBV. We previously reported the identification of a series of -hydroxypyridinedione (HPD) imines that effectively inhibit the HBV RNase H. In our effort to further explore the HPD scaffold, we designed, synthesized, and evaluated 18 novel HPD oximes, as well as 4 structurally related minoxidil derivatives and 2 barbituric acid counterparts. The new analogs were docked on the RNase H active site and all proved able to coordinate the two Mg ions in the catalytic site. All of the new HPDs effectively inhibited the viral replication in cell assays exhibiting EC values in the low μM range (1.1-7.7 μM) with low cytotoxicity, resulting in selectivity indexes (SI) of up to 92, one of the highest reported to date among HBV RNase H inhibitors. Our findings expand the structure-activity relationships on the HPD scaffold, facilitating the development of even more potent anti-HBV agents.
Topics: Hepatitis B virus; Virus Replication; Antiviral Agents; Ribonuclease H; Humans; Structure-Activity Relationship; Molecular Docking Simulation; Catalytic Domain; Oximes; Molecular Structure; Hep G2 Cells; Enzyme Inhibitors
PubMed: 38931006
DOI: 10.3390/molecules29122942