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1.
Toxicol Appl Pharmacol ; 404: 115182, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-694488

ABSTRACT

Due to the pandemic of coronavirus disease 2019, the use of disinfectants is rapidly increasing worldwide. Didecyldimethylammonium chloride (DDAC) is an EPA-registered disinfectant, it was also a component in humidifier disinfectants that had caused idiopathic pulmonary diseases in Korea. In this study, we identified the possible pulmonary toxic response and mechanism using human bronchial epithelial (BEAS-2B) cells and mice. First, cell viability decreased sharply at a 4 µg/mL of concentration. The volume of intracellular organelles and the ROS level reduced, leading to the formation of apoptotic bodies and an increase of the LDH release. Secretion of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and matrix metalloproteinase-1 also significantly increased. More importantly, lamellar body-like structures were formed in both the cells and mice exposed to DDAC, and the expression of both the indicator proteins for lamellar body (ABCA3 and Rab11a) and surfactant proteins (A, B, and D) was clearly enhanced. In addition, chronic fibrotic pulmonary lesions were notably observed in mice instilled twice (weekly) with DDAC (500 µg), ultimately resulting in death. Taken together, we suggest that disruption of pulmonary surfactant homeostasis may contribute to DDAC-induced cell death and subsequent pathophysiology and that the formation of lamellar body-like structures may play a role as the trigger. In addition, we propose that the cause of sudden death of mice exposed to DDAC should be clearly elucidated for the safe application of DDAC.


Subject(s)
Betacoronavirus/drug effects , Cell Survival/drug effects , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Quaternary Ammonium Compounds/toxicity , Animals , Apoptosis/drug effects , Cell Line , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Humans , Male , Mice , Mice, Inbred ICR , Quaternary Ammonium Compounds/administration & dosage
2.
Signal Transduct Target Ther ; 5(1): 125, 2020 07 13.
Article in English | MEDLINE | ID: covidwho-654479

ABSTRACT

Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson's diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Heat-Shock Proteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Host-Pathogen Interactions/drug effects , Pneumonia, Viral/drug therapy , Antiviral Agents/chemical synthesis , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Chromatin Assembly and Disassembly/drug effects , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gene Expression Regulation , Heat-Shock Proteins/agonists , Heat-Shock Proteins/antagonists & inhibitors , Heat-Shock Proteins/metabolism , Heterogeneous-Nuclear Ribonucleoproteins/agonists , Heterogeneous-Nuclear Ribonucleoproteins/antagonists & inhibitors , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Host-Pathogen Interactions/genetics , Humans , Molecular Targeted Therapy/methods , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , RNA Polymerase II/genetics , RNA Polymerase II/metabolism , RNA Precursors/genetics , RNA Precursors/metabolism , Severity of Illness Index , Signal Transduction , Transcription, Genetic/drug effects , Virus Replication/drug effects
3.
Int J Mol Sci ; 21(14)2020 Jul 14.
Article in English | MEDLINE | ID: covidwho-649852

ABSTRACT

Effective treatment of retinal diseases with adeno-associated virus (AAV)-mediated gene therapy is highly dependent on the proportion of successfully transduced cells. However, due to inflammatory reactions at high vector doses, adjunctive treatment may be necessary to enhance the therapeutic outcome. Hydroxychloroquine and chloroquine are anti-malarial drugs that have been successfully used in the treatment of autoimmune diseases. Evidence suggests that at high concentrations, hydroxychloroquine and chloroquine can impact viral infection and replication by increasing endosomal and lysosomal pH. This effect has led to investigations into the potential benefits of these drugs in the treatment of viral infections, including human immunodeficiency virus and severe acute respiratory syndrome coronavirus-2. However, at lower concentrations, hydroxychloroquine and chloroquine appear to exert immunomodulatory effects by inhibiting nucleic acid sensors, including toll-like receptor 9 and cyclic GMP-AMP synthase. This dose-dependent effect on their mechanism of action supports observations of increased viral infections associated with lower drug doses. In this review, we explore the immunomodulatory activity of hydroxychloroquine and chloroquine, their impact on viral infections, and their potential to improve the efficacy and safety of retinal gene therapy by reducing AAV-induced immune responses. The safety and practicalities of delivering hydroxychloroquine into the retina will also be discussed.


Subject(s)
Chloroquine/therapeutic use , Genetic Therapy , Hydroxychloroquine/therapeutic use , Retinal Diseases/therapy , Virus Diseases/drug therapy , Animals , Betacoronavirus/drug effects , Chloroquine/pharmacology , Dependovirus/genetics , Humans , Hydroxychloroquine/pharmacology , Immunomodulation/drug effects , Retinal Diseases/pathology
4.
Nat Commun ; 11(1): 2750, 2020 06 02.
Article in English | MEDLINE | ID: covidwho-680538

ABSTRACT

Influenza viruses annually kill 290,000-650,000 people worldwide. Antivirals can reduce death tolls. Baloxavir, the recently approved influenza antiviral, inhibits initiation of viral mRNA synthesis, whereas oseltamivir, an older drug, inhibits release of virus progeny. Baloxavir blocks virus replication more rapidly and completely than oseltamivir, reducing the duration of infectiousness. Hence, early baloxavir treatment may indirectly prevent transmission. Here, we estimate impacts of ramping up and accelerating baloxavir treatment on population-level incidence using a new model that links viral load dynamics from clinical trial data to between-host transmission. We estimate that ~22 million infections and >6,000 deaths would have been averted in the 2017-2018 epidemic season by administering baloxavir to 30% of infected cases within 48 h after symptom onset. Treatment within 24 h would almost double the impact. Consequently, scaling up early baloxavir treatment would substantially reduce influenza morbidity and mortality every year. The development of antivirals against the SARS-CoV2 virus that function like baloxavir might similarly curtail transmission and save lives.


Subject(s)
Antiviral Agents/therapeutic use , Epidemics , Influenza, Human/drug therapy , Orthomyxoviridae/drug effects , Oxazines/therapeutic use , Pyridines/therapeutic use , Thiepins/therapeutic use , Triazines/therapeutic use , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Cell Proliferation , Coronavirus Infections/drug therapy , Humans , Influenza, Human/virology , Oseltamivir/pharmacology , Oseltamivir/therapeutic use , Oxazines/pharmacology , Pandemics , Pneumonia, Viral/drug therapy , Public Health , Pyridines/pharmacology , RNA, Messenger/metabolism , Seasons , Thiepins/pharmacology , Triazines/pharmacology , Viral Load , Virus Replication/drug effects
5.
ACS Nano ; 14(8): 9364-9388, 2020 08 25.
Article in English | MEDLINE | ID: covidwho-646861

ABSTRACT

The SARS-Cov-2 pandemic has spread worldwide during 2020, setting up an uncertain start of this decade. The measures to contain infection taken by many governments have been extremely severe by imposing home lockdown and industrial production shutdown, making this the biggest crisis since the second world war. Additionally, the continuous colonization of wild natural lands may touch unknown virus reservoirs, causing the spread of epidemics. Apart from SARS-Cov-2, the recent history has seen the spread of several viral pandemics such as H2N2 and H3N3 flu, HIV, and SARS, while MERS and Ebola viruses are considered still in a prepandemic phase. Hard nanomaterials (HNMs) have been recently used as antimicrobial agents, potentially being next-generation drugs to fight viral infections. HNMs can block infection at early (disinfection, entrance inhibition) and middle (inside the host cells) stages and are also able to mitigate the immune response. This review is focused on the application of HNMs as antiviral agents. In particular, mechanisms of actions, biological outputs, and limitations for each HNM will be systematically presented and analyzed from a material chemistry point-of-view. The antiviral activity will be discussed in the context of the different pandemic viruses. We acknowledge that HNM antiviral research is still at its early stage, however, we believe that this field will rapidly blossom in the next period.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/therapy , Nanostructures/therapeutic use , Pandemics , Pneumonia, Viral/therapy , Adaptive Immunity , Betacoronavirus/drug effects , Betacoronavirus/physiology , Betacoronavirus/ultrastructure , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Delivery Systems , Fullerenes/therapeutic use , Host Microbial Interactions/drug effects , Humans , Immunity, Innate , Metal Nanoparticles/therapeutic use , Models, Biological , Nanotechnology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Reactive Oxygen Species/therapeutic use , Virus Internalization/drug effects
6.
Nano Lett ; 20(7): 5367-5375, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-628240

ABSTRACT

Geometry-matching has been known to benefit the formation of stable biological interactions in natural systems. Herein, we report that the spiky nanostructures with matched topography to the influenza A virus (IAV) virions could be used to design next-generation advanced virus inhibitors. We demonstrated that nanostructures with spikes between 5 and 10 nm bind significantly better to virions than smooth nanoparticles, due to the short spikes inserting into the gaps of glycoproteins of the IAV virion. Furthermore, an erythrocyte membrane (EM) was coated to target the IAV, and the obtained EM-coated nanostructures could efficiently prevent IAV virion binding to the cells and inhibit subsequent infection. In a postinfection study, the EM-coated nanostructures reduced >99.9% virus replication at the cellular nontoxic dosage. We predict that such a combination of geometry-matching topography and cellular membrane coating will also push forward the development of nanoinhibitors for other virus strains, including SARS-CoV-2.


Subject(s)
Betacoronavirus/ultrastructure , Coronavirus Infections/virology , Nanostructures/ultrastructure , Pneumonia, Viral/virology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Binding Sites , Coronavirus Infections/drug therapy , Drug Design , Humans , Influenza A virus/drug effects , Influenza A virus/ultrastructure , Microscopy, Electron , Models, Biological , Nanotechnology , Pandemics , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/drug effects , Spike Glycoprotein, Coronavirus/ultrastructure , Virus Internalization/drug effects
7.
Nan Fang Yi Ke Da Xue Xue Bao ; 40(4): 586-594, 2020 Apr 30.
Article in Chinese | MEDLINE | ID: covidwho-749256

ABSTRACT

Since the outbreak of coronavirus disease 2019 (COVID-19) in the late 2019, a variety of antiviral drugs have been used in the first-line clinical trial. The Diagnostic and Treatment Protocol for COVID-19 (Trial Version 6) in China recommends chloroquine phosphate for the first time as an anti-coronavirus trial drug. As a classic drug for treatment of malaria and rheumatism, chloroquine phosphate has been used clinically for more than 80 years, and has also shown good results in the treatment of various viral infections. As the plasma drug concentration varies greatly among different races and individuals and due to its narrow treatment window, chloroquine in likely to accumulate in the body to cause toxicity. Among the treatment regimens recommended for COVID-19, reports concerning the safety of a short-term high-dose chloroquine regimen remain scarce. In this review, the authors summarize the current research findings of chloroquine phosphate in the treatment of COVID-19, and examine the pharmacokinetic characteristics, antiviral therapy, the therapeutic mechanism and safety of chloroquine.


Subject(s)
Betacoronavirus/drug effects , Chloroquine/analogs & derivatives , Coronavirus Infections , Pandemics , Pneumonia, Viral , Antiviral Agents , China , Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Humans , Pneumonia, Viral/drug therapy
8.
Trials ; 21(1): 766, 2020 Sep 05.
Article in English | MEDLINE | ID: covidwho-745676

ABSTRACT

OBJECTIVES: To investigate the potential efficacy of Acacia Senegal extract Gum Arabic (GA) supplementation as immunomodulatory and anti-inflammatory dietary intervention among newly diagnosed COVID 19 Sudanese patients. To study the effect of GA on the level of cytokines, TNFα, IL8, IL6 IL10, CRP and the viral load. Secondary outcomes will be the effect of GA oral intake on mortality rate and days of hospital admission. TRIAL DESIGN: Quadruple blind, randomized placebo-controlled clinical trial Phase II & III. Prospective, two-arm, parallel-group, randomised (1:1 allocation ratio) superiority trial of oral GA among seropositive COVID-19 patients. PARTICIPANTS: Inclusion criteria: COVID-19 infected (newly diagnosed) as proved by real-time PCR within 72 hours of PCR. Age 8-90 years Both genders Exclusion criteria: Intubated patients on parenteral treatment Allergy to Gum Arabic The study will be conducted in COVID Isolation Centres and Soba University Hospital Khartoum State Sudan. INTERVENTION AND COMPARATOR: Experimental: Intervention Group This arm will receive 100% natural Gum Arabic provided in a powder form in 30-grams-dose once daily for four weeks Placebo Comparator: Control group: This group will be provided with pectin powder provided as one-gram-dose once daily for four weeks Both GA and placebo will be in addition to standard care treatment based on local clinical guidelines. MAIN OUTCOMES: Mean change from baseline score of Immune Response to end of the trial. Changes of the level of Tumor Necrosis Factor (TNFα), interleukin IL8, IL6, and IL10 from the baseline values (Four weeks from the start of randomization). Mortality rate: The percentage of deaths among COVID 19 patients received Gum Arabic compared to placebo (Four weeks from the start of randomization]). RANDOMISATION: Randomization (1:1 allocation ratio) and will be conducted using a sequence of computer-generated random numbers by an independent individual. Each participating centre will be assigned a special code generated by the computer. The randomization will be kept by the PI and a research assistant. BLINDING (MASKING): Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 110 eligible patients will be randomly assigned to either GA (n=55) or placebo (n=55) groups. TRIAL STATUS: Protocol Version no 2, 30th June 2020. Recruitment will start on 15th September 2020. The intended completion date is 15th January 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04381871 . Date of trial registration: 11 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Gum Arabic/therapeutic use , Immunologic Factors/therapeutic use , Pneumonia, Viral/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Child , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Female , Gum Arabic/adverse effects , Host Microbial Interactions , Humans , Immunologic Factors/adverse effects , Male , Middle Aged , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Prospective Studies , Randomized Controlled Trials as Topic , Time Factors , Treatment Outcome , Young Adult
9.
Trials ; 21(1): 758, 2020 Sep 03.
Article in English | MEDLINE | ID: covidwho-745011

ABSTRACT

OBJECTIVES: Tocilizumab is a humanized monoclonal antibody which targets and inhibits interleukin-6 (IL-6) and has demonstrated efficacy in treating diseases associated with hyper-inflammation. Data are suggestive of tocilizumab as a potential treatment for patients with COVID-19 infection. The aim of this study is to determine the safety and efficacy of standard dose versus low dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation on time to intubation, non-invasive ventilation and/or all-cause mortality. TRIAL DESIGN: This trial is a phase 2, open label, two-stage, multicentre, randomised trial. PARTICIPANTS: Adult subjects with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation requiring admission to hospital at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Inclusion criteria Aged 18 years or older. Confirmed SARS-CoV2 infection (as defined by positive PCR). Evidence of hyper inflammatory state as evidenced by at least three of the following: Documented temperature >38°C in the past 48 hours, IL6 >40 pg/ml, or in its absence D-dimer >1.5 µgFEU /ml, Elevated CRP (>100mg/L) and/or a three-fold increase since presentation, Elevated ferritin X5 ULN, Elevated LDH (above the ULN), Elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging. Moderate to severe respiratory failure as defined by PaO2/FiO2≤300mmHg. INTERVENTION AND COMPARATOR: Intervention for participants in this trial is SOC plus Tocilizumab compared to SOC alone (comparator). For Stage 1, following randomisation, subjects will receive either (Arm 1) SOC alone or (Arm 2) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes. Once stage 1 has fully recruited, subsequent participants will be enrolled directly into Stage 2 and receive either (Arm 1) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes or (Arm 2) SOC plus Tocilizumab (standard single dose - 4mg/kg, infused over 60 minutes). MAIN OUTCOMES: The primary endpoint for this study is the time to a composite primary endpoint of progression to intubation and ventilation, non-invasive ventilation or death within 28 days post randomisation. RANDOMISATION: Eligible patients will be randomised (1:1) using a central register. Randomisation will be performed through an interactive, web-based electronic data capturing database. In stage 1, eligible participants will be randomised (1:1) to (Arm 1) SOC alone or to (Arm 2) SOC with single dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. In stage 2, eligible participants will be randomised (1:1) to receive either (Arm 1) single, standard dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes or (Arm 2) reduced dose (4mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. BLINDING: This study is open label. The study will not be blinded to investigators, subjects, or medical or nursing staff. The trial statistician will be blinded for data analysis and will be kept unaware of treatment group assignments. To facilitate this, the randomisation schedule will be drawn up by an independent statistician and objective criteria were defined for the primary outcome to minimize potential bias. NUMBERS TO BE RANDOMISED: In stage 1, 90 subjects will be randomised 1:1, 45 to SOC and 45 subjects to SOC plus Tocilizumab (8mg/kg, infused over 60 minutes). In stage 2, sample size calculation for the dose evaluation stage will use data generated from stage 1 using the same primary endpoint as in stage 1. TRIAL STATUS: The COVIRL002 trial (Protocol version 1.4, 13th May 2020) commenced in May 2020 at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Recruitment is proceeding with the aim to achieve the target sample size on or before April 2021. TRIAL REGISTRATION: COVIRL002 was registered 25 June 2020 under EudraCT number: 2020-001767-86 and Protocol identification: UCDCRC/20/02. FULL PROTOCOL: The full protocol for COVIRL002 is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Anti-Inflammatory Agents/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Betacoronavirus/pathogenicity , Clinical Trials, Phase II as Topic , Coronavirus Infections/diagnosis , Coronavirus Infections/mortality , Coronavirus Infections/virology , Disease Progression , Host Microbial Interactions , Humans , Intubation, Intratracheal , Ireland , Multicenter Studies as Topic , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Respiration, Artificial , Severity of Illness Index , Time Factors , Treatment Outcome
10.
Molecules ; 25(17)2020 Sep 01.
Article in English | MEDLINE | ID: covidwho-742825

ABSTRACT

Over the years, coronaviruses (CoV) have posed a severe public health threat, causing an increase in mortality and morbidity rates throughout the world. The recent outbreak of a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current Coronavirus Disease 2019 (COVID-19) pandemic that affected more than 215 countries with over 23 million cases and 800,000 deaths as of today. The situation is critical, especially with the absence of specific medicines or vaccines; hence, efforts toward the development of anti-COVID-19 medicines are being intensively undertaken. One of the potential therapeutic targets of anti-COVID-19 drugs is the angiotensin-converting enzyme 2 (ACE2). ACE2 was identified as a key functional receptor for CoV associated with COVID-19. ACE2, which is located on the surface of the host cells, binds effectively to the spike protein of CoV, thus enabling the virus to infect the epithelial cells of the host. Previous studies showed that certain flavonoids exhibit angiotensin-converting enzyme inhibition activity, which plays a crucial role in the regulation of arterial blood pressure. Thus, it is being postulated that these flavonoids might also interact with ACE2. This postulation might be of interest because these compounds also show antiviral activity in vitro. This article summarizes the natural flavonoids with potential efficacy against COVID-19 through ACE2 receptor inhibition.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/physiology , Biological Products/pharmacology , Coronavirus Infections/virology , Flavonoids/pharmacology , Pneumonia, Viral/virology , Angiotensin-Converting Enzyme Inhibitors/chemistry , Antiviral Agents/chemistry , Biological Products/chemistry , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Disease Susceptibility , Flavonoids/chemistry , Humans , Life Cycle Stages , Models, Molecular , Pandemics , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Population Surveillance , Structure-Activity Relationship
11.
In Vivo ; 34(5): 3027-3028, 2020.
Article in English | MEDLINE | ID: covidwho-740632

ABSTRACT

The FDA-approved drugs raloxifene and bazedoxifene could be among the best candidates to prevent mortality in severe COVID-19 patients. Raloxifene and bazedoxifene inhibit IL-6 signaling at therapeutic doses, suggesting they have the potential to prevent the cytokine storm, ARDS and mortality in severe COVID-19 patients, as is being shown with humanized antibodies blocking IL-6 signaling. In addition, raloxifene and bazedoxifene are selective estrogen receptor modulators with strong antiviral activity.


Subject(s)
Coronavirus Infections/drug therapy , Indoles/pharmacology , Pneumonia, Viral/drug therapy , Raloxifene Hydrochloride/pharmacology , Respiratory Distress Syndrome, Adult/drug therapy , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Receptors, Estrogen/antagonists & inhibitors , Respiratory Distress Syndrome, Adult/prevention & control , Respiratory Distress Syndrome, Adult/virology , Selective Estrogen Receptor Modulators/pharmacology , Signal Transduction/drug effects
12.
In Vivo ; 34(5): 3023-3026, 2020.
Article in English | MEDLINE | ID: covidwho-740631

ABSTRACT

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One drug that has attracted interest is the antiparasitic compound ivermectin, a macrocyclic lactone derived from the bacterium Streptomyces avermitilis. We carried out a docking study to determine if ivermectin might be able to attach to the SARS-CoV-2 spike receptor-binding domain bound with ACE2. MATERIALS AND METHODS: We used the program AutoDock Vina Extended to perform the docking study. RESULTS: Ivermectin docked in the region of leucine 91 of the spike and histidine 378 of the ACE2 receptor. The binding energy of ivermectin to the spike-ACE2 complex was -18 kcal/mol and binding constant was 5.8 e-08. CONCLUSION: The ivermectin docking we identified may interfere with the attachment of the spike to the human cell membrane. Clinical trials now underway should determine whether ivermectin is an effective treatment for SARS-Cov2 infection.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Ivermectin/chemistry , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/drug therapy , Betacoronavirus/chemistry , Betacoronavirus/pathogenicity , Binding Sites/drug effects , Cell Membrane/drug effects , Coronavirus Infections/virology , Drug Repositioning , Histidine/chemistry , Humans , Ivermectin/therapeutic use , Leucine/chemistry , Molecular Docking Simulation , Pandemics , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral/virology , Streptomyces/chemistry
15.
Molecules ; 25(17)2020 Aug 28.
Article in English | MEDLINE | ID: covidwho-740497

ABSTRACT

A pandemic caused by the novel coronavirus (SARS-CoV-2 or COVID-19) began in December 2019 in Wuhan, China, and the number of newly reported cases continues to increase. More than 19.7 million cases have been reported globally and about 728,000 have died as of this writing (10 August 2020). Recently, it has been confirmed that the SARS-CoV-2 main protease (Mpro) enzyme is responsible not only for viral reproduction but also impedes host immune responses. The Mpro provides a highly favorable pharmacological target for the discovery and design of inhibitors. Currently, no specific therapies are available, and investigations into the treatment of COVID-19 are lacking. Therefore, herein, we analyzed the bioactive phytocompounds isolated by gas chromatography-mass spectroscopy (GC-MS) from Tinospora crispa as potential COVID-19 Mpro inhibitors, using molecular docking study. Our analyses unveiled that the top nine hits might serve as potential anti-SARS-CoV-2 lead molecules, with three of them exerting biological activity and warranting further optimization and drug development to combat COVID-19.


Subject(s)
Antiviral Agents/chemistry , Betacoronavirus/chemistry , Phytochemicals/chemistry , Protease Inhibitors/chemistry , Tinospora/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/classification , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Catalytic Domain , Coronavirus Infections/drug therapy , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/genetics , Cysteine Endopeptidases/metabolism , Drug Discovery , Gas Chromatography-Mass Spectrometry , Gene Expression , Humans , Kinetics , Molecular Docking Simulation , Pandemics , Phytochemicals/classification , Phytochemicals/isolation & purification , Phytochemicals/pharmacology , Pneumonia, Viral/drug therapy , Protease Inhibitors/classification , Protease Inhibitors/isolation & purification , Protease Inhibitors/pharmacology , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Substrate Specificity , Thermodynamics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
16.
Cien Saude Colet ; 25(9): 3517-3554, 2020 Sep.
Article in English, Portuguese | MEDLINE | ID: covidwho-740424

ABSTRACT

This work aimed to evaluate the effects of drug therapies for coronavirus infections. Rapid systematic review with search in the MEDLINE, EMBASE, Cochrane, BVS, Global Index Medicus, Medrix, bioRxiv, Clinicaltrials.gov and International Clinical Trials Registry Platform databases. Thirty-six studies evaluating alternative drugs against SARS, SARS-CoV-2 and MERS were included. Most of the included studies were conducted in China with an observational design for the treatment of COVID-19. The most studied treatments were with antimalarials and antivirals. In antimalarial, the meta-analysis of two studies with 180 participants did not identify the benefit of hydroxychloroquine concerning the negative viral load via real-time polymerase chain reaction, and the use of antivirals compared to standard care was similar regarding outcomes. The available scientific evidence is preliminary and of low methodological quality, which suggests caution when interpreting its results. Research that evaluates comparative efficacy in randomized, controlled clinical trials, with adequate follow-up time and with the methods properly disclosed and subject to scientific peer review is required. A periodic update of this review is recommended.


Subject(s)
Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Severe Acute Respiratory Syndrome/drug therapy , Antimalarials/administration & dosage , Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , Coronavirus Infections/virology , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Pandemics , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , SARS Virus/drug effects , SARS Virus/isolation & purification , Severe Acute Respiratory Syndrome/virology
17.
Medicine (Baltimore) ; 99(35): e21927, 2020 Aug 28.
Article in English | MEDLINE | ID: covidwho-740206

ABSTRACT

BACKGROUND: The number of patients infected with novel coronavirus disease (COVID-19) has exceeded 10 million in 2020, and a large proportion of them are asymptomatic. At present, there is still no effective treatment for this disease. Traditional Chinese medicine (TCM) shows a good therapeutic effect on COVID-19, especially for asymptomatic patients. According to the search results, we found that although there are many studies on COVID-19, there are no studies targeting asymptomatic infections. Therefore, we design a network meta-analysis (NMA) to evaluate the therapeutic effect of TCM on asymptomatic COVID-19. METHODS: We will search Chinese and English databases to collect all randomized controlled trials (RCTs) of TCM combined with conventional western medicine or using only TCM to treat asymptomatic COVID-19 from December 2019 to July 2020. Then, two investigators will independently filter the articles, extract data, and evaluate the risk of bias. We will conduct a Bayesian NMA to evaluate the effects of different therapies. All data will be processed by Stata 16.0 and WinBUGS. RESULTS: This study will evaluate the effectiveness of various treatments for asymptomatic COVID-19. The outcome indicators include the time when the nucleic acid turned negative, the proportion of patients with disease progression, changes in laboratory indicators, and the side effects of drugs. CONCLUSION: This analysis will further improve the treatment of asymptomatic COVID-19. INPLASY REGISTRATION NUMBER: INPLASY202070022.


Subject(s)
Combined Modality Therapy/methods , Coronavirus Infections/therapy , Medicine, Chinese Traditional/methods , Pneumonia, Viral/therapy , Asymptomatic Infections/therapy , Bayes Theorem , Betacoronavirus/drug effects , Betacoronavirus/isolation & purification , Coronavirus Infections/drug therapy , Humans , Network Meta-Analysis , Pandemics , Research Design , Treatment Outcome
18.
Sci Rep ; 10(1): 14290, 2020 08 31.
Article in English | MEDLINE | ID: covidwho-738236

ABSTRACT

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/virology , Drug Discovery , Pneumonia, Viral/virology , Amides/chemistry , Amides/pharmacology , Antiviral Agents/chemistry , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/diagnosis , Drug Discovery/methods , Humans , Lopinavir/chemistry , Lopinavir/pharmacology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Pandemics , Pneumonia, Viral/diagnosis , Pyrazines/chemistry , Pyrazines/pharmacology , Ritonavir/chemistry , Ritonavir/pharmacology
19.
Clin Sci (Lond) ; 134(17): 2235-2241, 2020 09 18.
Article in English | MEDLINE | ID: covidwho-738221

ABSTRACT

Human serine protease inhibitors (serpins) are the main inhibitors of serine proteases, but some of them also have the capability to effectively inhibit cysteine proteases. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) main protease (Mpro) is a chymotrypsin-type cysteine protease that is needed to produce functional proteins essential for virus replication and transcription. Serpin traps its target proteases by presenting a reactive center loop (RCL) as protease-specific cleavage site, resulting in protease inactivation. Mpro target sites with its active site serine and other flanking residues can possibly interact with serpins. Alternatively, RCL cleavage site of serpins with known evidence of inhibition of cysteine proteases can be replaced by Mpro target site to make chimeric proteins. Purified chimeric serpin can possibly inhibit Mpro that can be assessed indirectly by observing the decrease in ability of Mpro to cleave its chromogenic substrate. Chimeric serpins with best interaction and active site binding and with ability to form 1:1 serpin-Mpro complex in human plasma can be assessed by using SDS/PAGE and Western blot analysis with serpin antibody. Trapping SARS-CoV-2 Mpro cysteine protease using cross-class serpin cysteine protease inhibition activity is a novel idea with significant therapeutic potential.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Serpins/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/therapeutic use , Betacoronavirus/enzymology , Blotting, Western , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Electrophoresis, Polyacrylamide Gel , Humans , Pandemics , Pneumonia, Viral/virology , Serpins/therapeutic use , Viral Nonstructural Proteins/chemistry
20.
J Int Med Res ; 48(8): 300060520949077, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-737978

ABSTRACT

The emergence of coronavirus disease 2019 (COVID-19) in December 2019 has resulted in over 20 million cases and 741,808 deaths globally, affecting more than 200 countries. COVID-19 was declared a pandemic on 11 March 2020 by the World Health Organization. The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). There is limited information on COVID-19, and treatment has so far focused on supportive care and use of repurposed drugs. COVID-19 can be transmitted via person-to-person contact through droplet spread. Some of the recommended precautionary measures to reduce the rate of disease spread include social distancing, good hygiene practices, and avoidance of crowded areas. These measures are effective because the droplets are heavy and can only travel approximately 1 meter in the air, settling quickly on fixed surfaces. Promising strategies to combat SARS-CoV-2 include discovery of therapeutic targets/drugs and vaccines. In this review, we summarize the epidemiology, pathophysiology, and diagnosis of COVID-19. We also address the mechanisms of action of approved repurposed drugs for therapeutic management of the disease.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/pathogenicity , Communicable Disease Control/organization & administration , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Age Factors , Alanine/analogs & derivatives , Alanine/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/genetics , Chloroquine/therapeutic use , Communicable Disease Control/methods , Coronavirus Infections/diagnosis , Coronavirus Infections/physiopathology , Drug Repositioning , Humans , Incidence , Personal Protective Equipment/supply & distribution , Pneumonia, Viral/diagnosis , Pneumonia, Viral/physiopathology , Quarantine/methods , Quarantine/organization & administration , Severity of Illness Index , Social Distance , Survival Analysis
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