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Emerging pharmacotherapy for COVID-19.
Lipworth, B, Kuo, CR, Chan, R
The journal of the Royal College of Physicians of Edinburgh. 2020;(2):133-137
Abstract
Broadly speaking, pharmacological treatments for COVID-19 can be divided into those acting on upstream pathways early on in the disease process via suppression of viral replication or by inhibiting cell entry, and those acting on downstream pathways later on via selective attenuation of the adaptive immune cytokine-mediated inflammatory response. The antiviral drug remdesivir has been shown to shorten duration of disease while interferon beta-1b may speed up viral clearance. The results with hydroxychloroquine have thus far been rather disappointing. Trials with selective cytokine blockers including anti-interleukin-1 (anti-IL-1) and anti-interleukin-6 (anti-IL-6), have shown some promise in more severe cases, with further confirmation being required from large-scale phase-3 randomised controlled trials. The likelihood is that combination therapy addressing both upstream and downstream pathways may be required to prevent progression of severe COVID-19 infection in susceptible older patients with comorbidities and we believe further studies are now warranted to specifically target such at-risk groups who are more prone to worse outcomes.
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Lactoferrin as potential preventative and adjunct treatment for COVID-19.
Chang, R, Ng, TB, Sun, WZ
International journal of antimicrobial agents. 2020;(3):106118
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Abstract
The coronavirus disease 2019 (COVID-19) pandemic is rapidly advancing across the globe despite drastic public and personal health measures. Antivirals and nutritional supplements have been proposed as potentially useful against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes COVID-19, but few have been clinically established. Lactoferrin (Lf) is a naturally occurring, non-toxic glycoprotein that is orally available as a nutritional supplement and has established in vitro antiviral efficacy against a wide range of viruses, including SARS-CoV, a closely related coronavirus to SARS-CoV-2. Furthermore, Lf possesses unique immunomodulatory and anti-inflammatory effects that may be especially relevant to the pathophysiology of severe COVID-19 cases. Here we review the underlying biological mechanisms of Lf as an antiviral and immune regulator, and propose its unique potential as a preventative and adjunct treatment for COVID-19. We hope that further research and development of Lf nutritional supplementation would establish its role for COVID-19.
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The effects of β1 and β1+2 adrenergic receptor blockade on the exercise-induced mobilization and ex vivo expansion of virus-specific T cells: implications for cellular therapy and the anti-viral immune effects of exercise.
Kunz, HE, Agha, NH, Hussain, M, LaVoy, EC, Smith, KA, Mylabathula, P, Diak, D, Baker, FL, O'Connor, DP, Bond, RA, et al
Cell stress & chaperones. 2020;(6):993-1012
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Abstract
The adoptive transfer of donor-derived virus-specific T cells (VSTs) is an effective treatment for infections following allogeneic hematopoietic cell transplantation. Acute exercise mobilizes effector lymphocytes and VSTs to the circulation and augments the ex vivo manufacture of VSTs. This study determined if β2 adrenergic receptor (AR) signaling precipitated the VST response to acute exercise. Healthy participants (n = 12) completed 30 min of steady-state cycling exercise after ingesting a placebo, a β1 + 2 AR antagonist (nadolol) or a β1 AR antagonist (bisoprolol). Circulating VSTs to cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (AdV) antigens were enumerated before and after exercise, and peripheral blood mononuclear cells were cultured with viral peptides for 8 days to expand multi-VSTs. Compared with placebo, nadolol blunted the exercise-induced mobilization of CMV-VSTs (Δ VSTs/100,000 CD3+ T cells = 93 ± 104 vs. 22 ± 91 for placebo and nadolol, respectively; p = 0.036), while bisoprolol did not, despite both drugs evoking similar reductions in exercising heart rate and blood pressure. Circulating AdV and EBV VSTs (VSTs/mL blood) only increased after exercise with placebo. Although not significant, nadolol partially mitigated exercise-induced increases in multi-VST expansion, particularly in participants that demonstrated an exercise-induced increase in VST expansion. We conclude that exercise-induced enhancements in VST mobilization and expansion are at least partially β2 AR mediated, thus highlighting a role for the β2 AR in targeted therapy for the augmentation of VST immune cell therapeutics in the allogeneic adoptive transfer setting. Moreover, long-term regular exercise may provide additional viral protection in the host through frequent β2 AR-dependent mobilization and redistribution of VSTs cumulated with each bout of exercise.
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Global multi-omics and systems pharmacological strategy unravel the multi-targeted therapeutic potential of natural bioactive molecules against COVID-19: An in silico approach.
Muthuramalingam, P, Jeyasri, R, Valliammai, A, Selvaraj, A, Karthika, C, Gowrishankar, S, Pandian, SK, Ramesh, M, Chen, JT
Genomics. 2020;(6):4486-4504
Abstract
Understanding the immunological behavior of COVID-19 cases at molecular level is essential for therapeutic development. In this study, multi-omics and systems pharmacology analyses were performed to unravel the multi-targeted mechanisms of novel bioactives to combat COVID-19. Immuno-transcriptomic dataset of healthy controls and COVID-19 cases was retrieved from ArrayExpress. Phytocompounds from ethnobotanical plants were collected from PubChem. Differentially expressed 98 immune genes associated with COVID-19 were derived through NetworkAnalyst 3.0. Among 259 plant derived compounds, 154 compounds were targeting 13 COVID-19 immune genes involved in diverse signaling pathways. In addition, pharmacological properties of these phytocompounds were compared with COVID-19 drugs prescribed by WHO, and 25 novel phytocompounds were found to be more efficient with higher bioactive scores. The current study unravels the virogenomic signatures which can serve as therapeutic targets and identified phytocompounds with anti-COVID-19 efficacy. However, further experimental validation is essential to bring out these molecules as commercial drug candidates.
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TRIM25 and its emerging RNA-binding roles in antiviral defense.
Choudhury, NR, Heikel, G, Michlewski, G
Wiley interdisciplinary reviews. RNA. 2020;(4):e1588
Abstract
The innate immune system is the body's first line of defense against viruses, with pattern recognition receptors (PRRs) recognizing molecules unique to viruses and triggering the expression of interferons and other anti-viral cytokines, leading to the formation of an anti-viral state. The tripartite motif containing 25 (TRIM25) is an E3 ubiquitin ligase thought to be a key component in the activation of signaling by the PRR retinoic acid-inducible gene I protein (RIG-I). TRIM25 has recently been identified as an RNA-binding protein, raising the question of whether its RNA-binding activity is important for its role in innate immunity. Here, we review TRIM25's mechanisms and pathways in noninfected and infected cells. We also introduce models that explain how TRIM25 binding to RNA could modulate its functions and play part in the antiviral response. These findings have opened new lines of investigations into functional and molecular roles of TRIM25 and other E3 ubiquitin ligases in cell biology and control of pathogenic infections. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition.
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Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity.
Sturley, SL, Rajakumar, T, Hammond, N, Higaki, K, Márka, Z, Márka, S, Munkacsi, AB
Journal of lipid research. 2020;(7):972-982
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.
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Immune-Boosting, Antioxidant and Anti-inflammatory Food Supplements Targeting Pathogenesis of COVID-19.
Mrityunjaya, M, Pavithra, V, Neelam, R, Janhavi, P, Halami, PM, Ravindra, PV
Frontiers in immunology. 2020;:570122
Abstract
The COVID-19 is an acute and contagious disease characterized by pneumonia and ARDS. The disease is caused by SARS-CoV-2, which belongs to the family of Coronaviridae along with MERS-CoV and SARS-CoV-1. The virus has the positive-sense RNA as its genome encoding for ~26 proteins that work together for the virus survival, replication, and spread in the host. The virus gets transmitted through the contact of aerosol droplets from infected persons. The pathogenesis of COVID-19 is highly complex and involves suppression of host antiviral and innate immune response, induction of oxidative stress followed by hyper inflammation described as the "cytokine storm," causing the acute lung injury, tissue fibrosis, and pneumonia. Currently, several vaccines and drugs are being evaluated for their efficacy, safety, and for determination of doses for COVID-19 and this requires considerable time for their validation. Therefore, exploring the repurposing of natural compounds may provide alternatives against COVID-19. Several nutraceuticals have a proven ability of immune-boosting, antiviral, antioxidant, anti-inflammatory effects. These include Zn, vitamin D, vitamin C, curcumin, cinnamaldehyde, probiotics, selenium, lactoferrin, quercetin, etc. Grouping some of these phytonutrients in the right combination in the form of a food supplement may help to boost the immune system, prevent virus spread, preclude the disease progression to severe stage, and further suppress the hyper inflammation providing both prophylactic and therapeutic support against COVID-19.
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Evaluation of mechanisms of action of re-purposed drugs for treatment of COVID-19.
Rajaiah, R, Abhilasha, KV, Shekar, MA, Vogel, SN, Vishwanath, BS
Cellular immunology. 2020;:104240
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Abstract
Coronavirus disease 2019 (COVID-19) is a global health emergency caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The rapid worldwide spread of SARS-CoV-2 infection has necessitated a global effort to identify effective therapeutic strategies in the absence of vaccine. Among the re-purposed drugs being tested currently, hydroxychloroquine (HCQ), without or with zinc ion (Zn++) and the antibiotic azithromycin (AZM), has been administered to prevent or treat patients with COVID-19. The outcome of multiple clinical studies on HCQ has been mixed. Zn++ interferes with viral replication by inhibiting replicative enzymes and its entry into cells may be facilitated by HCQ. Another immunomodulatory drug, methotrexate (MTX), is well known for its ability to mitigate overactive immune system by upregulating the anti-inflammatory protein, A20. However, its beneficial effect in treating COVID-19 has not drawn much attention. This review provides an overview of the virology of SARS-CoV-2 and an analysis of the mechanisms by which these anti-inflammatory agents may act in the treatment of COVID-19 patients. We propose a rationale for the combinatorial use of these re-purposed drugs that may help to combat this ongoing pandemic health emergency.
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Critical care management of adults with community-acquired severe respiratory viral infection.
Arabi, YM, Fowler, R, Hayden, FG
Intensive care medicine. 2020;(2):315-328
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Abstract
With the expanding use of molecular assays, viral pathogens are increasingly recognized among critically ill adult patients with community-acquired severe respiratory illness; studies have detected respiratory viral infections (RVIs) in 17-53% of such patients. In addition, novel pathogens including zoonotic coronaviruses like the agents causing Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and the 2019 novel coronavirus (2019 nCoV) are still being identified. Patients with severe RVIs requiring ICU care present typically with hypoxemic respiratory failure. Oseltamivir is the most widely used neuraminidase inhibitor for treatment of influenza; data suggest that early use is associated with reduced mortality in critically ill patients with influenza. At present, there are no antiviral therapies of proven efficacy for other severe RVIs. Several adjunctive pharmacologic interventions have been studied for their immunomodulatory effects, including macrolides, corticosteroids, cyclooxygenase-2 inhibitors, sirolimus, statins, anti-influenza immune plasma, and vitamin C, but none is recommended at present in severe RVIs. Evidence-based supportive care is the mainstay for management of severe respiratory viral infection. Non-invasive ventilation in patients with severe RVI causing acute hypoxemic respiratory failure and pneumonia is associated with a high likelihood of transition to invasive ventilation. Limited existing knowledge highlights the need for data regarding supportive care and adjunctive pharmacologic therapy that is specific for critically ill patients with severe RVI. There is a need for more pragmatic and efficient designs to test different therapeutics both individually and in combination.
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Potential interventions for novel coronavirus in China: A systematic review.
Zhang, L, Liu, Y
Journal of medical virology. 2020;(5):479-490
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Abstract
An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. In the absence of treatment for this virus, there is an urgent need to find alternative methods to control the spread of disease. Here, we have conducted an online search for all treatment options related to coronavirus infections as well as some RNA-virus infection and we have found that general treatments, coronavirus-specific treatments, and antiviral treatments should be useful in fighting COVID-19. We suggest that the nutritional status of each infected patient should be evaluated before the administration of general treatments and the current children's RNA-virus vaccines including influenza vaccine should be immunized for uninfected people and health care workers. In addition, convalescent plasma should be given to COVID-19 patients if it is available. In conclusion, we suggest that all the potential interventions be implemented to control the emerging COVID-19 if the infection is uncontrollable.