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1.
J Cardiovasc Med (Hagerstown) ; 22(9): 711-715, 2021 Sep 01.
Article in English | MEDLINE | ID: covidwho-1496885

ABSTRACT

CoronaVIrus Disease-19 (COVID-19) had a huge impact on human health and economy. However, to this date, the effects of the pandemic on the training of young cardiologists are only partially known. To assess the consequences of the pandemic on the education of the cardiologists in training, we performed a 23-item national survey that has been delivered to 1443 Italian cardiologists in training, registered in the database of the Italian Society of Cardiology (SIC). Six hundred and thirty-three cardiologists in training participated in the survey. Ninety-five percent of the respondents affirmed that the training programme has been somewhat stopped or greatly jeopardized by the pandemic. For 61% of the fellows in training (FITs), the pandemic had a negative effect on their education. Moreover, 59% of the respondents believe that they would not be able to fill the gap gained during that period over the rest of their training. A negative impact on the psycho-physical well being has been reported by 86% of the FITs. The COVID-19 pandemic had an unparalleled impact on the education, formation and mental state of the cardiologists in training. Regulatory agencies, universities and politicians should make a great effort in the organization and reorganization of the teaching programs of the cardiologists of tomorrow.


Subject(s)
COVID-19 , Cardiologists , Cardiology/education , Communicable Disease Control , Education , Internship and Residency , COVID-19/epidemiology , COVID-19/prevention & control , Cardiologists/education , Cardiologists/psychology , Cardiologists/standards , Clinical Competence/standards , Communicable Disease Control/methods , Communicable Disease Control/organization & administration , Education/organization & administration , Education/standards , Fellowships and Scholarships/methods , Fellowships and Scholarships/statistics & numerical data , Humans , Internship and Residency/methods , Internship and Residency/organization & administration , Internship and Residency/standards , Italy/epidemiology , Needs Assessment , SARS-CoV-2 , Societies, Medical/statistics & numerical data , Surveys and Questionnaires
2.
Antimicrob Agents Chemother ; 65(8): e0049121, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1486471

ABSTRACT

In the present report, we describe two small molecules with broad-spectrum antiviral activity. These drugs block the formation of the nodosome. The studies were prompted by the observation that infection of human fetal brain cells with Zika virus (ZIKV) induces the expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a host factor that was found to promote ZIKV replication and spread. A drug that targets NOD2 was shown to have potent broad-spectrum antiviral activity against other flaviviruses, alphaviruses, enteroviruses, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Another drug that inhibits receptor-interacting serine/threonine protein kinase 2 (RIPK2), which functions downstream of NOD2, also decreased the replication of these pathogenic RNA viruses. The antiviral effect of this drug was particularly potent against enteroviruses. The broad-spectrum action of nodosome-targeting drugs is mediated in part by the enhancement of the interferon response. Together, these results suggest that further preclinical investigation of nodosome inhibitors as potential broad-spectrum antivirals is warranted.


Subject(s)
Arboviruses , COVID-19 , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Humans , SARS-CoV-2 , Virus Replication
3.
Autophagy ; 17(8): 2048-2050, 2021 08.
Article in English | MEDLINE | ID: covidwho-1393103

ABSTRACT

TMEM41B and VMP1, two endoplasmic reticulum (ER)-resident transmembrane proteins, play important roles in regulating the formation of lipid droplets (LDs), autophagy initiation, and viral infection. However, the biochemical functions of TMEM41B and VMP1 are unclear. A lipids distribution screen suggested TMEM41B and VMP1 are critical to the normal distribution of cholesterol and phosphatidylserine. Biochemical analyses unveiled that TMEM41B and VMP1 have scramblase activity. These findings shed light on the mechanism by which TMEM41B and VMP1 regulate LD formation, lipids distribution, macroautophagy, and viral infection.


Subject(s)
Autophagy/physiology , Membrane Proteins/metabolism , Phospholipid Transfer Proteins/metabolism , Animals , Autophagosomes/metabolism , Humans , Macroautophagy/physiology
4.
Front Chem ; 9: 679776, 2021.
Article in English | MEDLINE | ID: covidwho-1389150

ABSTRACT

Targeting the polyamine biosynthetic pathway by inhibiting ornithine decarboxylase (ODC) is a powerful approach in the fight against diverse viruses, including SARS-CoV-2. Difluoromethylornithine (DFMO, eflornithine) is the best-known inhibitor of ODC and a broad-spectrum, unique therapeutical agent. Nevertheless, its pharmacokinetic profile is not perfect, especially when large doses are required in antiviral treatment. This article presents a holistic study focusing on the molecular and supramolecular structure of DFMO and the design of its analogues toward the development of safer and more effective formulations. In this context, we provide the first deep insight into the supramolecular system of DFMO supplemented by a comprehensive, qualitative and quantitative survey of non-covalent interactions via Hirshfeld surface, molecular electrostatic potential, enrichment ratio and energy frameworks analysis visualizing 3-D topology of interactions in order to understand the differences in the cooperativity of interactions involved in the formation of either basic or large synthons (Long-range Synthon Aufbau Modules, LSAM) at the subsequent levels of well-organized supramolecular self-assembly, in comparison with the ornithine structure. In the light of the drug discovery, supramolecular studies of amino acids, essential constituents of proteins, are of prime importance. In brief, the same amino-carboxy synthons are observed in the bio-system containing DFMO. DFT calculations revealed that the biological environment changes the molecular structure of DFMO only slightly. The ADMET profile of structural modifications of DFMO and optimization of its analogue as a new promising drug via molecular docking are discussed in detail.

5.
Biomol NMR Assign ; 15(1): 85-89, 2021 04.
Article in English | MEDLINE | ID: covidwho-1384621

ABSTRACT

Among the proteins encoded by the SARS-CoV-2 RNA, nsP3 (non-structural Protein3) is the largest multi-domain protein. Its role is multifaceted and important for the viral life cycle. Nonetheless, regarding the specific role of each domain there are many aspects of their function that have to be investigated. SARS Unique Domains (SUDs), constitute the nsP3c region of the nsP3, and were observed for the first time in SARS-CoV. Two of them, namely SUD-N (the first SUD) and the SUD-M (sequential to SUD-N), exhibit structural homology with nsP3b ("X" or macro domain); indeed all of them are folded in a three-layer α/ß/α sandwich. On the contrary, they do not exhibit functional similarities, like ADP-ribose binding properties and ADP-ribose hydrolase activity. There are reports that suggest that these two SUDs may exhibit a binding selectivity towards G-oligonucleotides, a feature which may contribute to the characterization of their role in the formation of the replication/transcription viral complex (RTC) and of the interaction of various viral "components" with the host cell. While the structures of these domains of SARS-CoV-2 have not been determined yet, SUDs interaction with oligonucleotides and/or RNA molecules may provide a platform for drug discovery. Here, we report the almost complete NMR backbone and side-chain resonance assignment (1H,13C,15N) of SARS-CoV-2 SUD-N protein, and the NMR chemical shift-based prediction of the secondary structure elements. These data may be exploited for its 3D structure determination and the screening of chemical compounds libraries, which may alter SUD-N function.


Subject(s)
Coronavirus Papain-Like Proteases/chemistry , Magnetic Resonance Spectroscopy , SARS-CoV-2/chemistry , Carbon Isotopes , Drug Design , Hydrogen , Nitrogen Isotopes , Oligonucleotides/chemistry , Protein Domains , Protein Structure, Secondary , Virus Replication
6.
Phytochem Rev ; : 1-40, 2021 Jun 04.
Article in English | MEDLINE | ID: covidwho-1384539

ABSTRACT

Flavaglines are formed by cycloaddition of a flavonoid nucleus with a cinnamic acid moiety representing a typical chemical character of the genus Aglaia of the family Meliaceae. Based on biosynthetic considerations 148 derivatives are grouped together into three skeletal types representing 77 cyclopenta[b]benzofurans, 61 cyclopenta[bc]benzopyrans, and 10 benzo[b]oxepines. Apart from different hydroxy, methoxy, and methylenedioxy groups of the aromatic rings, important structural variation is created by different substitutions and stereochemistries of the central cyclopentane ring. Putrescine-derived bisamides constitute important building blocks occurring as cyclic 2-aminopyrrolidines or in an open-chained form, and are involved in the formation of pyrimidinone flavaglines. Regarding the central role of cinnamic acid in the formation of the basic skeleton, rocagloic acid represents a biosynthetic precursor from which aglafoline- and rocaglamide-type cyclopentabenzofurans can be derived, while those of the rocaglaol-type are the result of decarboxylation. Broad-based comparison revealed characteristic substitution trends which contribute as chemical markers to natural delimitation and grouping of taxonomically problematic Aglaia species. A wide variety of biological activities ranges from insecticidal, antifungal, antiprotozoal, and anti-inflammatory properties, especially to pronounced anticancer and antiviral activities. The high insecticidal activity of flavaglines is comparable with that of the well-known natural insecticide azadirachtin. Comparative feeding experiments informed about structure-activity relationships and exhibited different substitutions of the cyclopentane ring essential for insecticidal activity. Parallel studies on the antiproliferative activity of flavaglines in various tumor cell lines revealed similar structural prerequisites that let expect corresponding molecular mechanisms. An important structural modification with very high cytotoxic potency was found in the benzofuran silvestrol characterized by an unusual dioxanyloxy subunit. It possessed comparable cytotoxicity to that of the natural anticancer compounds paclitaxel (Taxol®) and camptothecin without effecting normal cells. The primary effect was the inhibition of protein synthesis by binding to the translation initiation factor eIF4A, an ATP-dependent DEAD-box RNA helicase. Flavaglines were also shown to bind to prohibitins (PHB) responsible for regulation of important signaling pathways, and to inhibit the transcriptional factor HSF1 deeply involved in metabolic programming, survival, and proliferation of cancer cells. Flavaglines were shown to be not only promising anticancer agents but gained now also high expectations as agents against emerging RNA viruses like SARS-CoV-2. Targeting the helicase eIF4A with flavaglines was recently described as pan-viral strategy for minimizing the impact of future RNA virus pandemics.

7.
Biochimie ; 179: 229-236, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1326922

ABSTRACT

The ongoing pandemic of COVID-19 (Coronavirus Disease-2019), a respiratory disease caused by the novel coronavirus strain, SARS-CoV-2, has affected more than 42 million people already, with more than one million deaths worldwide (as of October 25, 2020). We are in urgent need of therapeutic interventions that target the host-virus interface, which requires a molecular understanding of the SARS-CoV-2 life-cycle. Like other positive-sense RNA viruses, coronaviruses remodel intracellular membranes to form specialized viral replication compartments, including double-membrane vesicles (DMVs), where viral RNA genome replication takes place. Here we review the current knowledge of the structure, lipid composition, function, and biogenesis of coronavirus-induced DMVs, highlighting the druggable viral and cellular factors that are involved in the formation and function of DMVs.


Subject(s)
Cell Membrane/metabolism , Coronavirus/physiology , Host Microbial Interactions , Virus Replication , Cell Membrane/virology , Humans , Molecular Targeted Therapy
8.
Biochem Biophys Res Commun ; 565: 64-71, 2021 08 06.
Article in English | MEDLINE | ID: covidwho-1251023

ABSTRACT

Neutrophil extracellular traps (NETs) are extracellular webs of DNA, histones and granular contents that are released by neutrophils to control infections. However, NETs that is not properly regulated can propagate inflammation and thrombosis. It was recognized that viruses can induce NETs. As a synthetic analog of viral double-stranded (ds) RNA, polyinosinic-polycytidylic acid [poly(I:C)] is known to induce inflammation and thrombosis. However, whether and how poly(I:C) modulates NETs remains unclear. Here, we have demonstrated that poly(I:C) induced extracellular DNA traps in human neutrophils in a dose-dependent manner. Further, poly(I:C) or dsRNA virus elevated the levels of myeloperoxidase-DNA complexes and citrullinated histone H3, which are specific markers of NETs, in both neutrophil supernatants and mouse plasma. Interestingly, a potent peptidylarginine deiminase 4 (PAD4) inhibitor, BB-CL-Amidine (BB-CLA) or PAD4 knockdown effectively prevented poly(I:C)-induced NETs formation and release. In addition, BB-CLA abrogated poly(I:C)-triggered neutrophil activation and infiltration, and vascular permeability in lungs. BB-CLA also attenuated poly(I:C)-induced thrombocytopenia in circulation, fibrin deposition and thrombus formation in tissues. Taken together, these results suggest that viral mimetic poly(I:C) may induce NETs-dependent inflammation and thrombosis through PAD4, and that inhibiting PAD4 may become a good strategy to protect against viral infection-caused inflammation/thrombosis-related pathological conditions of diseases.


Subject(s)
Extracellular Traps/drug effects , Inflammation/metabolism , Neutrophils/drug effects , Poly I-C/pharmacology , Protein-Arginine Deiminase Type 4/metabolism , Thrombosis/metabolism , Amidines/pharmacology , Animals , Cells, Cultured , Chlorocebus aethiops , Humans , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Neutrophil Activation/drug effects , Neutrophils/metabolism , Protein-Arginine Deiminase Type 4/antagonists & inhibitors , Thrombosis/pathology
9.
Pharmacol Res ; 158: 104950, 2020 08.
Article in English | MEDLINE | ID: covidwho-1318942

ABSTRACT

Patients affected by severe coronavirus induced disease-2019 (Covid-19) often experience hypoxemia due to alveolar involvement and endothelial dysfunction, which leads to the formation of micro thrombi in the pulmonary capillary vessels. Both hypoxemia and a prothrombotic diathesis have been associated with more severe disease and increased risk of death. To date, specific indications to treat this condition are lacking. This was a single center, investigator initiated, compassionate use, proof of concept, case control, phase IIb study (NCT04368377) conducted in the Intermediate Respiratory Care Unit of L. Sacco University Hospital in Milano, Italy. Our objective was to explore the effects of the administration of anti-platelet therapy on arterial oxygenation and clinical outcomes in patients with severe Covid-19 with hypercoagulability. We enrolled five consecutive patients with laboratory confirmed SARS-CoV-2 infection, severe respiratory failure requiring helmet continuous positive airway pressure (CPAP), bilateral pulmonary infiltrates and a pro-thrombotic state identified as a D-dimer > 3 times the upper limit of normal. Five patients matched for age, D-dimer value and SOFA score formed the control group. Beyond standard of care, treated patients received 25 µg/Kg/body weight tirofiban as bolus infusion, followed by a continuous infusion of 0.15 µg/Kg/body weight per minute for 48 hours. Before tirofiban, patients received acetylsalicylic acid 250 mg infusion and oral clopidogrel 300 mg; both were continued at a dose of 75 mg daily for 30 days. Fondaparinux2.5 mg/day sub-cutaneous was given for the duration of the hospital stay. All controls were receiving prophylactic or therapeutic dose heparin, according to local standard operating procedures. Treated patients consistently experienced a mean (SD) reduction in A-a O2 gradient of -32.6 mmHg (61.9, P = 0.154), -52.4 mmHg (59.4, P = 0.016) and -151.1 mmHg (56.6, P = 0.011; P = 0.047 vs. controls) at 24, 48 hours and 7 days after treatment. PaO2/FiO2 ratio increased by 52 mmHg (50, P = 0.172), 64 mmHg (47, P = 0.040) and 112 mmHg (51, P = 0.036) after 24, 48 hours and 7 days, respectively. All patients but one were successfully weaned from CPAP after 3 days. This was not true for the control group. No major adverse events were observed. Antiplatelet therapy might be effective in improving the ventilation/perfusion ratio in Covid-19 patients with severe respiratory failure. The effects might be sustained by the prevention and interference on forming clots in lung capillary vessels and by modulating megakaryocytes' function and platelet adhesion. Randomized clinical trials are urgently needed to confirm these results.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Hypoxia/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Thrombophilia/drug therapy , Aged , Aspirin/therapeutic use , COVID-19 , Clopidogrel/therapeutic use , Compassionate Use Trials , Coronavirus Infections/complications , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Hypoxia/complications , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , Proof of Concept Study , SARS-CoV-2 , Thrombophilia/blood , Thrombophilia/complications , Tirofiban/therapeutic use
10.
Front Immunol ; 12: 647824, 2021.
Article in English | MEDLINE | ID: covidwho-1268248

ABSTRACT

The exact role of innate immune cells upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their contribution to the formation of the corona virus-induced disease (COVID)-19 associated cytokine storm is not yet fully understood. We show that human in vitro differentiated myeloid dendritic cells (mDC) as well as M1 and M2 macrophages are susceptible to infection with SARS-CoV-2 but are not productively infected. Furthermore, infected mDC, M1-, and M2 macrophages show only slight changes in their activation status. Surprisingly, none of the infected innate immune cells produced the pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, or interferon (IFN)-α. Moreover, even in co-infection experiments using different stimuli, as well as non-influenza (non-flu) or influenza A (flu) viruses, only very minor IL-6 production was induced. In summary, we conclude that mDC and macrophages are unlikely the source of the first wave of cytokines upon infection with SARS-CoV-2.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Cytokines/metabolism , Dendritic Cells/metabolism , Inflammation Mediators/metabolism , Macrophages/metabolism , SARS-CoV-2/immunology , Biomarkers , COVID-19/virology , Dendritic Cells/immunology , Host-Pathogen Interactions , Humans , Immunity, Innate , Immunophenotyping , Macrophages/immunology , Viral Load
11.
Signal Transduct Target Ther ; 6(1): 233, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1265943

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has resulted in an unprecedented setback for global economy and health. SARS-CoV-2 has an exceptionally high level of transmissibility and extremely broad tissue tropism. However, the underlying molecular mechanism responsible for sustaining this degree of virulence remains largely unexplored. In this article, we review the current knowledge and crucial information about how SARS-CoV-2 attaches on the surface of host cells through a variety of receptors, such as ACE2, neuropilin-1, AXL, and antibody-FcγR complexes. We further explain how its spike (S) protein undergoes conformational transition from prefusion to postfusion with the help of proteases like furin, TMPRSS2, and cathepsins. We then review the ongoing experimental studies and clinical trials of antibodies, peptides, or small-molecule compounds with anti-SARS-CoV-2 activity, and discuss how these antiviral therapies targeting host-pathogen interaction could potentially suppress viral attachment, reduce the exposure of fusion peptide to curtail membrane fusion and block the formation of six-helix bundle (6-HB) fusion core. Finally, the specter of rapidly emerging SARS-CoV-2 variants deserves a serious review of broad-spectrum drugs or vaccines for long-term prevention and control of COVID-19 in the future.


Subject(s)
COVID-19/metabolism , COVID-19/therapy , Host-Pathogen Interactions , SARS-CoV-2/physiology , Virus Attachment , Virus Internalization , COVID-19/epidemiology , COVID-19/pathology , Humans
12.
J Med Virol ; 93(7): 4616-4619, 2021 07.
Article in English | MEDLINE | ID: covidwho-1263086

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) has been identified to be a mutation hot spot, with the P323L mutation being commonly observed in viral genomes isolated from North America. RdRp forms a complex with nonstructural proteins nsp7 and nsp8 to form the minimal replication/transcription machinery required for genome replication. As mutations in RdRp may affect formation of the RdRp-nsp7-nsp8 supercomplex, we analyzed viral genomes to identify mutations in nsp7 and nsp8 protein sequences. Based on in silico analysis of predicted structures of the supercomplex comprising of native and mutated proteins, we demonstrate that specific mutations in nsp7 and nsp8 proteins may have a role in stabilization of the replication/transcription complex.


Subject(s)
Coronavirus RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2/physiology , Viral Nonstructural Proteins/genetics , Viral Replication Compartments/chemistry , Amino Acid Sequence , Computer Simulation , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Genome, Viral , Humans , Models, Molecular , Mutation , Protein Stability , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Viral Replication Compartments/metabolism
13.
J Innate Immun ; 13(6): 345-358, 2021.
Article in English | MEDLINE | ID: covidwho-1245277

ABSTRACT

Regulation of proinflammatory cytokine expression is critical in the face of single-stranded RNA (ssRNA) virus infections. Many viruses, including coronavirus and influenza virus, wreak havoc on the control of cytokine expression, leading to the formation of detrimental cytokine storms. Understanding the regulation and interplay between inflammatory cytokines is critical to the identification of targets involved in controlling the induction of cytokine expression. In this study, we focused on how the antiviral cytokine interleukin-27 (IL-27) regulates signal transduction downstream of Toll-like receptor 7 (TLR7) and TLR8 ligation, which recognize endosomal single-stranded RNA. Given that IL-27 alters bacterial-sensing TLR expression on myeloid cells and can inhibit replication of single-stranded RNA viruses, we investigated whether IL-27 affects expression and function of TLR7 and TLR8. Analysis of IL-27-treated THP-1 monocytic cells and THP-1-derived macrophages revealed changes in mRNA and protein expression of TLR7 and TLR8. Although treatment with IL-27 enhanced TLR7 expression, only TLR8-mediated cytokine secretion was amplified. Furthermore, we demonstrated that imiquimod, a TLR7 agonist, inhibited cytokine and chemokine production induced by a TLR8 agonist, TL8-506. Delineating the immunomodulatory role of IL-27 on TLR7 and TLR8 responses provides insight into how myeloid cell TLR-mediated responses are regulated during virus infection.


Subject(s)
Interleukin-27/immunology , Macrophages/immunology , Monocytes/immunology , Toll-Like Receptor 7/immunology , Toll-Like Receptor 8/immunology , Cytokines/immunology , Humans , Immunomodulation , Inflammation , RNA, Messenger/metabolism , Signal Transduction , THP-1 Cells , Toll-Like Receptor 7/genetics , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/genetics , Toll-Like Receptor 8/metabolism
14.
Mar Drugs ; 19(5)2021 Apr 24.
Article in English | MEDLINE | ID: covidwho-1244064

ABSTRACT

Cyanobacteria are photosynthetic prokaryotic organisms which represent a significant source of novel, bioactive, secondary metabolites, and they are also considered an abundant source of bioactive compounds/drugs, such as dolastatin, cryptophycin 1, curacin toyocamycin, phytoalexin, cyanovirin-N and phycocyanin. Some of these compounds have displayed promising results in successful Phase I, II, III and IV clinical trials. Additionally, the cyanobacterial compounds applied to medical research have demonstrated an exciting future with great potential to be developed into new medicines. Most of these compounds have exhibited strong pharmacological activities, including neurotoxicity, cytotoxicity and antiviral activity against HCMV, HSV-1, HHV-6 and HIV-1, so these metabolites could be promising candidates for COVID-19 treatment. Therefore, the effective large-scale production of natural marine products through synthesis is important for resolving the existing issues associated with chemical isolation, including small yields, and may be necessary to better investigate their biological activities. Herein, we highlight the total synthesized and stereochemical determinations of the cyanobacterial bioactive compounds. Furthermore, this review primarily focuses on the biotechnological applications of cyanobacteria, including applications as cosmetics, food supplements, and the nanobiotechnological applications of cyanobacterial bioactive compounds in potential medicinal applications for various human diseases are discussed.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Cyanobacteria/chemistry , Cyanobacteria/physiology , SARS-CoV-2 , Antiviral Agents/chemistry , Aquatic Organisms , Humans
15.
Cell Discov ; 7(1): 38, 2021 May 25.
Article in English | MEDLINE | ID: covidwho-1243287

ABSTRACT

The newly emerging coronavirus SARS-CoV-2 causes severe lung disease and substantial mortality. How the virus evades host defense for efficient replication is not fully understood. In this report, we found that the SARS-CoV-2 nucleocapsid protein (NP) impaired stress granule (SG) formation induced by viral RNA. SARS-CoV-2 NP associated with the protein kinase PKR after dsRNA stimulation. SARS-CoV-2 NP did not affect dsRNA-induced PKR oligomerization, but impaired dsRNA-induced PKR phosphorylation (a hallmark of its activation) as well as SG formation. SARS-CoV-2 NP also targeted the SG-nucleating protein G3BP1 and impaired G3BP1-mediated SG formation. Deficiency of PKR or G3BP1 impaired dsRNA-triggered SG formation and increased SARS-CoV-2 replication. The NP of SARS-CoV also targeted both PKR and G3BP1 to impair dsRNA-induced SG formation, whereas the NP of MERS-CoV targeted PKR, but not G3BP1 for the impairment. Our findings suggest that SARS-CoV-2 NP promotes viral replication by impairing formation of antiviral SGs, and reveal a conserved mechanism on evasion of host antiviral responses by highly pathogenic human betacoronaviruses.

16.
Rev Environ Health ; 2021 May 24.
Article in English | MEDLINE | ID: covidwho-1238797

ABSTRACT

Nitrogen (N) is a critical component of food security, economy and planetary health. Human production of reactive nitrogen (Nr) via Haber-Bosch process and cultivation-induced biological N2 fixation (BNF) has doubled global N cycling over the last century. The most important beneficial effect of Nr is augmenting global food supplies due to increased crop yields. However, increased circulation of Nr in the environment is responsible for serious human health effects such as methemoglobinemia ("blue baby syndrome") and eutrophication of coastal and inland waters. Furthermore, ammonia (NH3) emission mainly from farming and animal husbandary impacts not only human health causing chronic lung disease, inflammation of human airways and irritation of eyes, sinuses and skin but is also involved in the formation of secondary particulate matter (PM) that plays a critical role in environment and human health. Nr also affects human health via global warming, depletion of stratospheric ozone layer resulting in greater intensity of ultra violet B rays (UVB) on the Earth's surface, and creation of ground-level ozone (through reaction of NO2 with O2). The consequential indirect human health effects of Nr include the spread of vector-borne pathogens, increased incidence of skin cancer, development of cataracts, and serious respiratory diseases, besides land degradation. Evidently, the strategies to reduce Nr and mitigate adverse environmental and human health impacts include plugging pathways of nitrogen transport and loss through runoff, leaching and emissions of NH3, nitrogen oxides (NO x ), and other N compounds; improving fertilizer N use efficiency; reducing regional disparity in access to N fertilizers; enhancing BNF to decrease dependence on chemical fertilizers; replacing animal-based proteins with plant-based proteins; adopting improved methods of livestock raising and manure management; reducing air pollution and secondary PM formation; and subjecting industrial and vehicular NO x emission to pollution control laws. Strategic implementation of all these presents a major challenge across the fields of agriculture, ecology and public health. Recent observations on the reduction of air pollution in the COVID-19 lockdown period in several world regions provide an insight into the achievability of long-term air quality improvement. In this review, we focus on complex relationships between Nr and human health, highlighting a wide range of beneficial and detrimental effects.

17.
J Autoimmun ; 121: 102663, 2021 07.
Article in English | MEDLINE | ID: covidwho-1233480

ABSTRACT

As the novel SARS-CoV-2 continues to infect numerous individuals worldwide, one of the leading approaches in dealing with the global health crisis is vaccination against the COVID-19. Due to recent reports, vaccination with ChAdOx1 nCov-19 (developed by Oxford and AstraZeneca) may result in a vaccine-induced catastrophic thrombotic thrombocytopenia disorder. Thus, as of March 16 of 2021, vaccination programs in 18 countries had been suspended until further examination, including Sweden, Germany and France. This disorder presents as extensive thrombosis in atypical sites, primarily in the cerebral venous, alongside thrombocytopenia and the production of autoantibody against platelet-factor 4 (PF4). PF4 autoantibody has the ability to binds the human FcRγIIA receptor of platelets and contribute to their aggregation. This rare adverse effect extremely resembles the clinical presentation of the classical immune-mediated HIT disorder, which occurs following exposure to heparin. Surprisingly, none of these patients had been pre-exposed to heparin before disease onset, leading to the hypothesis that a viral antigen from the vaccine had triggered the response. Importantly, COVID-19 had been associated with numerous autoimmune manifestations, including the production of pathogenic autoantibodies, new onset of autoimmune diseases and disorders. As the ChAdOx1 nCov-19 vaccination leads to the synthesis of specific SARS-CoV-2-proteins, they may trigger a production of PF4 autoantibody though molecular mimicry phenomena, while vaccination compounds lead to a rigorous bystander activation of immune cells. If existing, removing such homological sequences from the vaccine may eliminate this phenomenon. In contrast, it needs to be emphasized that the ChAdOx1 nCoV-19 vaccine was found to be safe and efficacious against symptomatic COVID-19 in randomized controlled trials, which included 23,848 participants from the UK, Brazil and South Africa.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/immunology , Purpura, Thrombocytopenic, Idiopathic/immunology , SARS-CoV-2/immunology , Antigens, Viral/immunology , Autoantibodies/immunology , COVID-19/pathology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Humans , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/pathology
18.
Antimicrob Agents Chemother ; 65(8): e0049121, 2021 07 16.
Article in English | MEDLINE | ID: covidwho-1232337

ABSTRACT

In the present report, we describe two small molecules with broad-spectrum antiviral activity. These drugs block the formation of the nodosome. The studies were prompted by the observation that infection of human fetal brain cells with Zika virus (ZIKV) induces the expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a host factor that was found to promote ZIKV replication and spread. A drug that targets NOD2 was shown to have potent broad-spectrum antiviral activity against other flaviviruses, alphaviruses, enteroviruses, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Another drug that inhibits receptor-interacting serine/threonine protein kinase 2 (RIPK2), which functions downstream of NOD2, also decreased the replication of these pathogenic RNA viruses. The antiviral effect of this drug was particularly potent against enteroviruses. The broad-spectrum action of nodosome-targeting drugs is mediated in part by the enhancement of the interferon response. Together, these results suggest that further preclinical investigation of nodosome inhibitors as potential broad-spectrum antivirals is warranted.


Subject(s)
Arboviruses , COVID-19 , Zika Virus Infection , Zika Virus , Antiviral Agents/pharmacology , Humans , SARS-CoV-2 , Virus Replication
19.
Science ; 372(6545): 941-948, 2021 05 28.
Article in English | MEDLINE | ID: covidwho-1205995

ABSTRACT

CRISPR-Cas systems recognize foreign genetic material using CRISPR RNAs (crRNAs). In type II systems, a trans-activating crRNA (tracrRNA) hybridizes to crRNAs to drive their processing and utilization by Cas9. While analyzing Cas9-RNA complexes from Campylobacter jejuni, we discovered tracrRNA hybridizing to cellular RNAs, leading to formation of "noncanonical" crRNAs capable of guiding DNA targeting by Cas9. Our discovery inspired the engineering of reprogrammed tracrRNAs that link the presence of any RNA of interest to DNA targeting with different Cas9 orthologs. This capability became the basis for a multiplexable diagnostic platform termed LEOPARD (leveraging engineered tracrRNAs and on-target DNAs for parallel RNA detection). LEOPARD allowed simultaneous detection of RNAs from different viruses in one test and distinguished severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its D614G (Asp614→Gly) variant with single-base resolution in patient samples.


Subject(s)
CRISPR-Associated Protein 9/metabolism , Clustered Regularly Interspaced Short Palindromic Repeats , RNA, Guide/genetics , RNA, Viral/analysis , RNA/analysis , RNA/genetics , SARS-CoV-2/genetics , Base Sequence , COVID-19/diagnosis , COVID-19/virology , COVID-19 Nucleic Acid Testing , CRISPR-Cas Systems , Campylobacter jejuni , Humans , Nucleic Acid Hybridization , RNA, Bacterial/genetics , RNA, Messenger/genetics , RNA, Viral/genetics , Spike Glycoprotein, Coronavirus/genetics
20.
Biochem Biophys Res Commun ; 558: 79-85, 2021 06 18.
Article in English | MEDLINE | ID: covidwho-1193239

ABSTRACT

During 2020, the COVID-19 pandemic affected almost 108 individuals. Quite a number of vaccines against COVID-19 were therefore developed, and a few recently received authorization for emergency use. Overall, these vaccines target specific viral proteins by antibodies whose synthesis is directly elicited or indirectly triggered by nucleic acids coding for the desired targets. Among these targets, the receptor binding domain (RBD) of COVID-19 spike protein (SP) does frequently occur in the repertoire of candidate vaccines. However, the immunogenicity of RBD per se is limited by its low molecular mass, and by a structural rearrangement of full-length SP accompanied by the detachment of RBD. Here we show that the RBD of COVID-19 SP can be conveniently produced in Escherichia coli when fused to a fragment of CRM197, a variant of diphtheria toxin currently used for a number of conjugated vaccines. In particular, we show that the CRM197-RBD chimera solubilized from inclusion bodies can be refolded and purified to a state featuring the 5 native disulphide bonds of the parental proteins, the competence in binding angiotensin-converting enzyme 2, and a satisfactory stability at room temperature. Accordingly, our observations provide compulsory information for the development of a candidate vaccine directed against COVID-19.


Subject(s)
Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Escherichia coli , Recombinant Fusion Proteins/biosynthesis , Recombinant Fusion Proteins/genetics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Bacterial Proteins/biosynthesis , Bacterial Proteins/isolation & purification , Base Sequence , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Escherichia coli/genetics , Escherichia coli/metabolism , Inclusion Bodies/chemistry , Inclusion Bodies/metabolism , Mass Spectrometry , Models, Molecular , Protein Refolding , Protein Stability , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/isolation & purification , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/biosynthesis , Spike Glycoprotein, Coronavirus/isolation & purification , Temperature , Time Factors
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