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1.
PLoS One ; 16(2): e0246803, 2021.
Article in English | MEDLINE | ID: covidwho-1079374

ABSTRACT

Niclosamide (NIC) has demonstrated promising in vitro antiviral efficacy against SARS-CoV-2, the causative agent of the COVID-19 pandemic. Though NIC is already FDA-approved, administration of the currently available oral formulation results in systemic drug levels that are too low for the inhibition of SARS-CoV-2. We hypothesized that the co-formulation of NIC with an endogenous protein, human lysozyme (hLYS), could enable the direct aerosol delivery of the drug to the respiratory tract as an alternative to oral delivery, thereby effectively treating COVID-19 by targeting the primary site of SARS-CoV-2 acquisition and spread. To test this hypothesis, we engineered and optimized composite particles containing NIC and hLYS suitable for delivery to the upper and lower airways via dry powder inhaler, nebulizer, and nasal spray. The novel formulation demonstrates potent in vitro and in vivo activity against two coronavirus strains, MERS-CoV and SARS-CoV-2, and may offer protection against methicillin-resistance staphylococcus aureus pneumonia and inflammatory lung damage occurring secondary to SARS-CoV-2 infections. The suitability of the formulation for all stages of the disease and low-cost development approach will ensure rapid clinical development and wide-spread utilization.


Subject(s)
Antiviral Agents/administration & dosage , Coronavirus Infections/drug therapy , Muramidase/administration & dosage , Niclosamide/administration & dosage , Administration, Inhalation , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Cell Line , Drug Compounding , Drug Delivery Systems/instrumentation , Dry Powder Inhalers , Humans , Mice, Transgenic , Middle East Respiratory Syndrome Coronavirus/drug effects , Muramidase/pharmacology , Muramidase/therapeutic use , Nasal Sprays , Niclosamide/pharmacology , Niclosamide/therapeutic use , /drug effects
3.
Ann Clin Microbiol Antimicrob ; 20(1): 8, 2021 Jan 18.
Article in English | MEDLINE | ID: covidwho-1067240

ABSTRACT

The Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has gained research attention worldwide, given the current pandemic. Nevertheless, a previous zoonotic and highly pathogenic coronavirus, the Middle East Respiratory Syndrome coronavirus (MERS-CoV), is still causing concern, especially in Saudi Arabia and neighbour countries. The MERS-CoV has been reported from respiratory samples in more than 27 countries, and around 2500 cases have been reported with an approximate fatality rate of 35%. After its emergence in 2012 intermittent, sporadic cases, nosocomial infections and many community clusters of MERS continued to occur in many countries. Human-to-human transmission resulted in the large outbreaks in Saudi Arabia. The inherent genetic variability among various clads of the MERS-CoV might have probably paved the events of cross-species transmission along with changes in the inter-species and intra-species tropism. The current review is drafted using an extensive review of literature on various databases, selecting of publications irrespective of favouring or opposing, assessing the merit of study, the abstraction of data and analysing data. The genome of MERS-CoV contains around thirty thousand nucleotides having seven predicted open reading frames. Spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins are the four main structural proteins. The surface located spike protein (S) of betacoronaviruses has been established to be one of the significant factors in their zoonotic transmission through virus-receptor recognition mediation and subsequent initiation of viral infection. Three regions in Saudi Arabia (KSA), Eastern Province, Riyadh and Makkah were affected severely. The epidemic progression had been the highest in 2014 in Makkah and Riyadh and Eastern Province in 2013. With a lurking epidemic scare, there is a crucial need for effective therapeutic and immunological remedies constructed on sound molecular investigations.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , /genetics , Middle East Respiratory Syndrome Coronavirus/genetics , Spike Glycoprotein, Coronavirus/genetics , /genetics , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Cross Infection/epidemiology , Cross Infection/virology , Disease Outbreaks , Humans , Middle East Respiratory Syndrome Coronavirus/isolation & purification , Phylogeny , RNA, Viral/genetics , Saudi Arabia/epidemiology
4.
SAR QSAR Environ Res ; 32(1): 51-70, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1066070

ABSTRACT

A Förster resonance energy transfer (FRET)-based assay was used to screen the FDA-approved compound library against the MERS-CoV helicase, an essential enzyme for virus replication within the host cell. Five compounds inhibited the helicase activity with submicromolar potencies (IC50, 0.73-1.65 µM) and ten compounds inhibited the enzyme with micromolar potencies (IC50, 19.6-502 µM). The molecular operating environment (MOE) was used to dock the identified inhibitors on the MERS-CoV helicase nucleotide binding. Strong inhibitors docked well in the nucleotide-binding site and established interactions with some of the essential residues. There was a reasonable correlation between the observed IC50 values and the MOE docking scores of the strong inhibitors (r 2 = 0.74), indicating the ability of the in silico docking model to predict the binding of strong inhibitors. In silico docking could be a useful complementary tool used with the FRET-based assay to predict new MERS-CoV helicase inhibitors. The identified inhibitors could potentially be used in the clinical development of new antiviral treatment for MERS-CoV and other coronavirus related diseases, including coronavirus disease 2019 (COVID-19).


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , DNA Helicases/drug effects , Enzyme Inhibitors/pharmacokinetics , Middle East Respiratory Syndrome Coronavirus/drug effects , Humans , Quantitative Structure-Activity Relationship , Virus Replication/drug effects
5.
Sci Data ; 8(1): 16, 2021 01 13.
Article in English | MEDLINE | ID: covidwho-1065922

ABSTRACT

Our systematic literature collection and annotation identified 106 chemical drugs and 31 antibodies effective against the infection of at least one human coronavirus (including SARS-CoV, SAR-CoV-2, and MERS-CoV) in vitro or in vivo in an experimental or clinical setting. A total of 163 drug protein targets were identified, and 125 biological processes involving the drug targets were significantly enriched based on a Gene Ontology (GO) enrichment analysis. The Coronavirus Infectious Disease Ontology (CIDO) was used as an ontological platform to represent the anti-coronaviral drugs, chemical compounds, drug targets, biological processes, viruses, and the relations among these entities. In addition to new term generation, CIDO also adopted various terms from existing ontologies and developed new relations and axioms to semantically represent our annotated knowledge. The CIDO knowledgebase was systematically analyzed for scientific insights. To support rational drug design, a "Host-coronavirus interaction (HCI) checkpoint cocktail" strategy was proposed to interrupt the important checkpoints in the dynamic HCI network, and ontologies would greatly support the design process with interoperable knowledge representation and reasoning.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Datasets as Topic , Drug Design , Humans , Knowledge Bases , Middle East Respiratory Syndrome Coronavirus , SARS Virus
6.
Viruses ; 13(1)2020 12 23.
Article in English | MEDLINE | ID: covidwho-1044046

ABSTRACT

Repurposing FDA-approved drugs that treat respiratory infections caused by coronaviruses, such as SARS-CoV-2 and MERS-CoV, could quickly provide much needed antiviral therapies. In the current study, the potency and cellular toxicity of four fluoroquinolones (enoxacin, ciprofloxacin, levofloxacin, and moxifloxacin) were assessed in Vero cells and A549 cells engineered to overexpress ACE2, the SARS-CoV-2 entry receptor. All four fluoroquinolones suppressed SARS-CoV-2 replication at high micromolar concentrations in both cell types, with enoxacin demonstrating the lowest effective concentration 50 value (EC50) of 126.4 µM in Vero cells. Enoxacin also suppressed the replication of MERS-CoV-2 in Vero cells at high micromolar concentrations. Cellular toxicity of levofloxacin was not found in either cell type. In Vero cells, minimal toxicity was observed following treatment with ≥37.5 µM enoxacin and 600 µM ciprofloxacin. Toxicity in both cell types was detected after moxifloxacin treatment of ≥300 µM. In summary, these results suggest that the ability of fluoroquinolones to suppress SARS-CoV-2 and MERS-CoV replication in cultured cells is limited.


Subject(s)
Anti-Bacterial Agents/pharmacology , Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Fluoroquinolones/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , /drug effects , A549 Cells , Animals , Cell Line , Chlorocebus aethiops , Ciprofloxacin/pharmacology , Enoxacin/pharmacology , Humans , Levofloxacin/pharmacology , Moxifloxacin/pharmacology , Vero Cells
7.
PLoS Pathog ; 17(1): e1009226, 2021 01.
Article in English | MEDLINE | ID: covidwho-1034956

ABSTRACT

Recombination is proposed to be critical for coronavirus (CoV) diversity and emergence of SARS-CoV-2 and other zoonotic CoVs. While RNA recombination is required during normal CoV replication, the mechanisms and determinants of CoV recombination are not known. CoVs encode an RNA proofreading exoribonuclease (nsp14-ExoN) that is distinct from the CoV polymerase and is responsible for high-fidelity RNA synthesis, resistance to nucleoside analogues, immune evasion, and virulence. Here, we demonstrate that CoVs, including SARS-CoV-2, MERS-CoV, and the model CoV murine hepatitis virus (MHV), generate extensive and diverse recombination products during replication in culture. We show that the MHV nsp14-ExoN is required for native recombination, and that inactivation of ExoN results in decreased recombination frequency and altered recombination products. These results add yet another critical function to nsp14-ExoN, highlight the uniqueness of the evolved coronavirus replicase, and further emphasize nsp14-ExoN as a central, completely conserved, and vulnerable target for inhibitors and attenuation of SARS-CoV-2 and future emerging zoonotic CoVs.


Subject(s)
/drug therapy , Coronavirus Infections/drug therapy , Exoribonucleases/pharmacology , Virus Replication/drug effects , Antiviral Agents/pharmacology , Coronavirus Infections/virology , Exoribonucleases/genetics , Humans , Recombination, Genetic/drug effects , Viral Nonstructural Proteins/genetics , Virus Replication/genetics
8.
Ann Intern Med ; 174(1): JC2, 2021 01.
Article in English | MEDLINE | ID: covidwho-1034497

ABSTRACT

SOURCE CITATION: Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379. 32887691.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Practice Guidelines as Topic , Betacoronavirus , Critical Illness , Humans , Pandemics , World Health Organization
9.
Molecules ; 26(2)2021 Jan 16.
Article in English | MEDLINE | ID: covidwho-1031148

ABSTRACT

The ongoing pandemic of severe acute respiratory syndrome (SARS), caused by the SARS-CoV-2 human coronavirus (HCoV), has brought the international scientific community before a state of emergency that needs to be addressed with intensive research for the discovery of pharmacological agents with antiviral activity. Potential antiviral natural products (NPs) have been discovered from plants of the global biodiversity, including extracts, compounds and categories of compounds with activity against several viruses of the respiratory tract such as HCoVs. However, the scarcity of natural products (NPs) and small-molecules (SMs) used as antiviral agents, especially for HCoVs, is notable. This is a review of 203 publications, which were selected using PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar, evaluates the available literature since the discovery of the first human coronavirus in the 1960s; it summarizes important aspects of structure, function, and therapeutic targeting of HCoVs as well as NPs (19 total plant extracts and 204 isolated or semi-synthesized pure compounds) with anti-HCoV activity targeting viral and non-viral proteins, while focusing on the advances on the discovery of NPs with anti-SARS-CoV-2 activity, and providing a critical perspective.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , Host-Pathogen Interactions/drug effects , SARS Virus/drug effects , /drug effects , Antiviral Agents/chemistry , Biological Products/chemistry , Coronavirus 229E, Human/drug effects , Coronavirus 229E, Human/physiology , Coronavirus Infections/drug therapy , Drug Evaluation, Preclinical , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , SARS Virus/chemistry , Viral Proteins/chemistry
11.
Int J Obes (Lond) ; 44(8): 1793-1799, 2020 08.
Article in English | MEDLINE | ID: covidwho-1023842

ABSTRACT

OBJECTIVE: Recent clinical trials have demonstrated that colchicine may have metabolic and cardiovascular and benefits in at-risk patients; however, the mechanisms through which colchicine may improve outcomes are still unclear. We sought to examine colchicine's effects on circulating inflammatory and metabolic molecules in adults with obesity and metabolic syndrome (MetS). METHODS: Blood samples were collected pre- and post-intervention during a double-blind randomized controlled trial in which 40 adults with obesity and MetS were randomized to colchicine 0.6 mg or placebo twice-daily for 3 months. Serum samples were analyzed for 1305 circulating factors using the SomaScan Platform. The Benjamini-Hochberg procedure was used to adjust the false discovery rate (FDR) for multiple testing. RESULTS: At baseline, age (48.0 ± 13.8 vs. 44.7 ± 10.3 years) and BMI (39.8 ± 6.4 vs. 41.8 ± 8.2 kg/m2) were not different between groups. After controlling for the FDR, 34 molecules were significantly changed by colchicine. Colchicine decreased concentrations of multiple inflammatory molecules, including C-reactive protein, interleukin 6, and resistin, in addition to vascular-related proteins (e.g., oxidized low-density lipoprotein receptor, phosphodiesterase 5A). Conversely, relative to placebo, colchicine significantly increased concentrations of eight molecules including secreted factors associated with metabolism and anti-thrombosis. CONCLUSIONS: In adults with obesity, colchicine significantly affected concentrations of proteins involved in the innate immune system, endothelial function and atherosclerosis, uncovering new mechanisms behind its cardiometabolic effects. Further research is warranted to investigate whether colchicine's IL-6 suppressive effects may be beneficial in COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Colchicine/therapeutic use , Coronavirus Infections/immunology , Metabolic Syndrome/complications , Metabolic Syndrome/immunology , Obesity/immunology , Pneumonia, Viral/immunology , Adult , Anti-Inflammatory Agents/pharmacology , Betacoronavirus/drug effects , C-Reactive Protein , Colchicine/pharmacology , Coronavirus Infections/drug therapy , Double-Blind Method , Female , Humans , Interleukin-6 , Male , Metabolic Syndrome/drug therapy , Middle Aged , Obesity/complications , Obesity/drug therapy , Pandemics , Pilot Projects , Pneumonia, Viral/drug therapy , Treatment Outcome , Young Adult
15.
Molecules ; 25(19)2020 Sep 23.
Article in English | MEDLINE | ID: covidwho-803884

ABSTRACT

The problem of treating viral infections is extremely relevant due to both the emergence of new viral diseases and to the low effectiveness of existing approaches to the treatment of known viral infections. This review focuses on the application of porphyrin, chlorin, and phthalocyanine series for combating viral infections by chemical and photochemical inactivation methods. The purpose of this review paper is to summarize the main approaches developed to date in the chemical and photodynamic inactivation of human and animal viruses using porphyrins and their analogues and to analyze and discuss the information on viral targets and antiviral activity of porphyrins, chlorins, of their conjugates with organic/inorganic compounds obtained in the last 10-15 years in order to identify the most promising areas.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Photochemotherapy/methods , Pneumonia, Viral/drug therapy , Porphyrins/pharmacology , Antiviral Agents/chemistry , Humans , Indoles/chemistry , Indoles/pharmacology , Pandemics , Photochemical Processes , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Porphyrins/chemistry , Virus Attachment/drug effects
16.
Antiviral Res ; 187: 105015, 2021 03.
Article in English | MEDLINE | ID: covidwho-1023450

ABSTRACT

The newly emerged severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) coronavirus initiated a pneumonia outbreak (COVID-19) that rapidly spread worldwide and quickly became a public health emergency of international concern; However to date, except Remdesivir, there are no clinically approved specific or effective medicines to prevent or treat COVID-19. Therefore, the development of novel treatments against coronavirus infections caused by the current SARS-CoV-2 virus, as well as other highly pathogenic human coronaviruses, represents an urgent unmet need. Stimulator of interferon genes (STING) plays a central role in host defense mechanisms against microbial infections. STING activation leads to the induction of both type I interferon and autophagy responses, which elicit strong inhibitory effect against the infections caused by a broad range of microbial pathogens. However, whether STING activation can impact infections from SARS-CoV-2 or other coronaviruses remains largely unknown. In this study, we investigated the anti-coronavirus activity triggered by STING activation. We discovered that dimeric amidobenzimidazole (diABZI), a synthetic small molecule STING receptor agonist, showed potent anti-coronavirus activity against both the common cold human coronavirus 229E (HCoV-229E) and SARS-CoV-2 in cell culture systems. In addition, we demonstrated that the antiviral activity of diABZI was dependent on the interferon pathway in HCoV-229E infected normal human fibroblast lung cells (MRC-5) and reconstituted primary human airway air-liquid interface (ALI) cultures. Furthermore, low-dose of diABZI treatment at 0.1 µM effectively reduced the SARS-CoV-2 viral load at the epithelial apical surface and prevented epithelial damage in the reconstituted primary human bronchial airway epithelial ALI system. Our findings have thus revealed the therapeutic potential of STING agonists, such as diABZI, as treatments for SARS-CoV-2 and other human coronavirus infections.


Subject(s)
Antiviral Agents/pharmacology , Benzimidazoles/pharmacology , Coronavirus 229E, Human/drug effects , Coronavirus Infections/drug therapy , Membrane Proteins/agonists , /drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Antiviral Agents/chemistry , Autophagy/drug effects , Bronchi/virology , Cell Line , Coronavirus Infections/virology , Epithelial Cells/virology , Humans , Interferon Type I/pharmacology , Lung/virology , Virus Replication
19.
Washington; Pan American Health Organization; Jan. 13, 2020. 171 p.
Non-conventional in English | LILACS (Americas) | ID: covidwho-1022980

ABSTRACT

This is the fourteenth edition of this database of evidence on potential therapeutic options for COVID-19, in which 68 therapeutic options are examined. This information will help investigators, policy makers, and prescribers navigate the flood of relevant data to ensure that management of COVID-19, at both individual and population levels, is based on the best available knowledge. This resource will be continually updated as more research is released into the public space.


Subject(s)
Humans , Pneumonia, Viral/drug therapy , Coronavirus Infections/drug therapy , Pandemics/prevention & control , Betacoronavirus/drug effects , Antiviral Agents/therapeutic use , Clinical Trials as Topic , Immunologic Factors/immunology
20.
Sheng Wu Gong Cheng Xue Bao ; 36(4): 605-611, 2020 Apr 25.
Article in Chinese | MEDLINE | ID: covidwho-1024807

ABSTRACT

Cyclophilin A (CypA) is a widely distributed and highly conserved protein in organisms. It has peptidyl-prolyl cis/trans isomerase activity and is a receptor for cyclosporin A (CsA). Coronaviruses are enveloped, single-stranded, positive-sense RNA viruses. Seven types of coronaviruses are currently known to infect humans, among which SARS-CoV, MERS-CoV, and SARS-CoV-2 are fatal for humans. It is well established that CypA is essential for the replication of various coronaviruses such as SARS-CoV, CoV-229E, CoV-NL63, and FCoV. Additionally, CsA and its derivatives (ALV, NIM811, etc.) have obvious inhibitory effects on a variety of coronaviruses. These results suggest that CypA is a potential antiviral target and the existing drug CsA might be used as an anti-coronavirus drug. At the end of 2019, SARS-CoV-2 raged in China, which seriously theatern human health and causes huge economic lases. In view of this, we describe the effects of CypA on the replication of coronaviruses and the antiviral activities of its inhibitors, which will provide the scientific basis and ideas for the development of antiviral drugs for SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections , Coronavirus/drug effects , Coronavirus/growth & development , Cyclophilin A/antagonists & inhibitors , Cyclosporine/pharmacology , Cyclosporine/therapeutic use , Pandemics , Pneumonia, Viral , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/growth & development , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Cyclosporine/chemistry , Humans , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS Virus/drug effects , SARS Virus/growth & development , Virus Replication/drug effects
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