scholarly journals Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

2020 ◽  
Author(s):  
Ruochen Zang ◽  
James Brett Case ◽  
Maria Florencia Gomez Castro ◽  
Zhuoming Liu ◽  
Qiru Zeng ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Molecular Basis ◽  
Enveloped Viruses ◽  
Late Endosomes ◽  
Wide Range ◽  
Therapeutic Development ◽  
Antiviral Activities ◽  
Catalyzed Membrane ◽  
Antiviral Mechanism ◽  
Enzymatic Product

AbstractCholesterol 25-hydroxylase (CH25H) is an interferon-stimulated gene (ISG) that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an ISG screen against VSV-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of virus replication. Mechanistically, internalized 25HC accumulates in the late endosomes and blocks cholesterol export, thereby restricting SARS-CoV-2 spike protein catalyzed membrane fusion. Our results highlight a unique antiviral mechanism of 25HC and provide the molecular basis for its possible therapeutic development.

scholarly journals Cholesterol 25-hydroxylase suppresses SARS-CoV-2 replication by blocking membrane fusion

2020 ◽  
Vol 117 (50) ◽  
pp. 32105-32113 ◽  
Author(s):  
Ruochen Zang ◽  
James Brett Case ◽  
Eylan Yutuc ◽  
Xiucui Ma ◽  
Sheng Shen ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Vesicular Stomatitis Virus ◽  
Molecular Basis ◽  
Enveloped Viruses ◽  
Late Endosomes ◽  
Wide Range ◽  
Therapeutic Development ◽  
Antiviral Activities ◽  
Vesicular Stomatitis ◽  
Catalyzed Membrane

Cholesterol 25-hydroxylase (CH25H) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.

scholarly journals Science-Based Strategies of Antiviral Coatings with Viricidal Properties for the COVID-19 Like Pandemics

Materials ◽  
2020 ◽  
Vol 13 (18) ◽  
pp. 4041
Author(s):  
Rakesh Pemmada ◽  
Xiaoxian Zhu ◽  
Madhusmita Dash ◽  
Yubin Zhou ◽  
Seeram Ramakrishna ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Polymeric Materials ◽  
Protective Equipment ◽  
Risk Of Infection ◽  
Functional Nanomaterials ◽  
Enveloped Viruses ◽  
Action Mode ◽  
Wide Range ◽  
Materials Used ◽  
Antiviral Mechanism

The worldwide, extraordinary outbreak of coronavirus pandemic (i.e., COVID-19) and other emerging viral expansions have drawn particular interest to the design and development of novel antiviral, and viricidal, agents, with a broad-spectrum of antiviral activity. The current indispensable challenge lies in the development of universal virus repudiation systems that are reusable, and capable of inactivating pathogens, thus reducing risk of infection and transmission. In this review, science-based methods, mechanisms, and procedures, which are implemented in obtaining resultant antiviral coated substrates, used in the destruction of the strains of the different viruses, are reviewed. The constituent antiviral members are classified into a few broad groups, such as polymeric materials, metal ions/metal oxides, and functional nanomaterials, based on the type of materials used at the virus contamination sites. The action mode against enveloped viruses was depicted to vindicate the antiviral mechanism. We also disclose hypothesized strategies for development of a universal and reusable virus deactivation system against the emerging COVID-19. In the surge of the current, alarming scenario of SARS-CoV-2 infections, there is a great necessity for developing highly-innovative antiviral agents to work against the viruses. We hypothesize that some of the antiviral coatings discussed here could exert an inhibitive effect on COVID-19, indicated by the results that the coatings succeeded in obtaining against other enveloped viruses. Consequently, the coatings need to be tested and authenticated, to fabricate a wide range of coated antiviral products such as masks, gowns, surgical drapes, textiles, high-touch surfaces, and other personal protective equipment, aimed at extrication from the COVID-19 pandemic.

Discovery of Some Antiviral Natural products to fight against Novel Corona Virus (SARS-CoV-2) using Insilico approach

2020 ◽  
Vol 23 ◽  
Author(s):  
Ashish Shah ◽  
Vaishali Patel ◽  
Bhumika Parmar
Keyword(s):  
Binding Affinity ◽  
Protein S ◽  
Docking Studies ◽  
Spike Protein ◽  
Enveloped Viruses ◽  
Bioactivity Prediction ◽  
Corona Virus ◽  
Main Protease ◽  
Antiviral Activities ◽  
Deadly Disease

Background: Novel Corona virus is a type of enveloped viruses with a single stranded RNA enclosing helical nucleocapsid. The envelope consists of spikes on the surface which are made up of proteins through which virus enters into human cells. Until now there is no specific drug or vaccine available to treat COVID-19 infection. In this scenario, reposting of drug or active molecules may provide rapid solution to fight against this deadly disease. Objective: We had selected 30 phytoconstituents from the different plants which are reported for antiviral activities against corona virus (CoVs) and performed insilico screening to find out phytoconstituents which have potency to inhibit specific target of novel corona virus. Methods: We had perform molecular docking studies on three different proteins of novel corona virus namely COVID-19 main protease (3CL pro), papain-like protease (PL pro) and spike protein (S) attached to ACE2 binding domain. The screening of the phytoconstituents on the basis of binding affinity compared to standard drugs. The validations of screened compounds were done using ADMET and bioactivity prediction. Results: We had screened five compounds biscoclaurine, norreticuline, amentoflavone, licoricidin and myricetin using insilico approach. All compounds found safe in insilico toxicity studies. Bioactivity prediction reviles that these all compounds may act through protease or enzyme inhibition. Results of compound biscoclaurine norreticuline were more interesting as this biscoclaurine had higher binding affinity for the target 3CLpro and PLpro targets and norreticuline had higher binding affinity for the target PLpro and Spike protein. Conclusion: Our study concludes that these compounds could be further explored rapidly as it may have potential to fight against COVID-19.

COVID-19: Opinion in Prevention and dietary based management hypothesis

Coronaviruses ◽  
2020 ◽  
Vol 01 ◽  
Author(s):  
Ashraf Talaat Youssef
Keyword(s):  
Fatty Acids ◽  
Saturated Fatty Acids ◽  
Lung Damage ◽  
Gastric Aspirate ◽  
Enveloped Viruses ◽  
Multiple Organs ◽  
Fold Reduction ◽  
Antiviral Activities

The pandemic of COVID-19 had started in Wuhan city china in late 2019 with a subsequent worldwide spread. The viral infection can seriousely affect multiple organs mainly lungs, kidneys, heart, liver and brain and may lead to respiratory, renal, cardiac or hepatic failure.Vascular thrombosis of unexplained mechanism that may lead to widespread blood clots in multiple organs and cytokine storms that result of overstimulation of the immune system subsequent of lung damage may lead to sudden decompensation due to hypotension and more damage to liver, kidney, brain or lungs.Until now no drug had proved efficient in getting rid of the problem and controlling the pandemic mainly depends on preventive measures.Many preventive measures can be considered to prevent the worldwide spread of viral transmission. Polyunsaturated long chain fatty acids (PUFAs) and the medium chain saturated fatty acids (MCSFAs) and their corresponding monoglycerides had high antiviral activities against the enveloped viruses which reach to more than 10,000 -fold reduction in the viral titres in vitro and in vivo after testing of its gastric aspirate, and can contribute to the systemic immunity against the enveloped viruses.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

scholarly journals Some notes on a historical perspective of panic disorder

2006 ◽  
Vol 55 (2) ◽  
pp. 154-160 ◽  
Author(s):  
Antonio Egidio Nardi
Keyword(s):  
Panic Disorder ◽  
20Th Century ◽  
19Th Century ◽  
Greek Mythology ◽  
Laboratory Studies ◽  
Biochemical Tests ◽  
Wide Range ◽  
Therapeutic Development ◽  
History Of ◽  
The 19Th Century

This article aims to describe important points in the history of panic disorder concept, as well as to highlight the importance of its diagnosis for clinical and research developments. Panic disorder has been described in several literary reports and folklore. One of the oldest examples lies in Greek mythology - the god Pan, responsible for the term panic. The first half of the 19th century witnessed the culmination of medical approach. During the second half of the 19th century came the psychological approach of anxiety. The 20th century associated panic disorder to hereditary, organic and psychological factors, dividing anxiety into simple and phobic anxious states. Therapeutic development was also observed in psychopharmacological and psychotherapeutic fields. Official classifications began to include panic disorder as a category since the third edition of the American Classification Manual (1980). Some biological theories dealing with etiology were widely discussed during the last decades of the 20th century. They were based on laboratory studies of physiological, cognitive and biochemical tests, as the false suffocation alarm theory and the fear network. Such theories were important in creating new diagnostic paradigms to modern psychiatry. That suggests the need to consider a wide range of historical variables to understand how particular features for panic disorder diagnosis have been developed and how treatment has emerged.

Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

2011 ◽  
Vol 439 (3) ◽  
pp. 349-378 ◽  
Author(s):  
Anthony J. Morgan ◽  
Frances M. Platt ◽  
Emyr Lloyd-Evans ◽  
Antony Galione
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Processes ◽  
Late Endosomes ◽  
Wide Range ◽  
Health And Disease ◽  
Lysosome Related Organelles ◽  
Cellular Compartments ◽  
Endosomal Vesicles ◽  
Intracellular Targets

Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

scholarly journals Exploring lectin–glycan interactions to combat COVID-19: Lessons acquired from other enveloped viruses

Glycobiology ◽  
2020 ◽  
Author(s):  
Luís Cláudio Nascimento da Silva ◽  
Juliana Silva Pereira Mendonça ◽  
Weslley Felix de Oliveira ◽  
Karla Lílian Rodrigues Batista ◽  
Adrielle Zagmignan ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Whole Blood ◽  
Therapeutic Approach ◽  
Viral Infections ◽  
Viral Envelope ◽  
Structural Studies ◽  
Human Coronavirus ◽  
Enveloped Viruses ◽  
Wide Range ◽  
Great Pressure

Abstract The emergence of a new human coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has imposed great pressure on the health system worldwide. The presence of glycoproteins on the viral envelope opens a wide range of possibilities for the application of lectins to address some urgent problems involved in this pandemic. In this work, we discuss the potential contributions of lectins from nonmammalian sources in the development of several fields associated with viral infections, most notably COVID-19. We review the literature on the use of nonmammalian lectins as a therapeutic approach against members of the Coronaviridae family, including recent advances in strategies of protein engineering to improve their efficacy. The applications of lectins as adjuvants for antiviral vaccines are also discussed. Finally, we present some emerging strategies employing lectins for the development of biosensors, microarrays, immunoassays and tools for purification of viruses from whole blood. Altogether, the data compiled in this review highlight the importance of structural studies aiming to improve our knowledge about the basis of glycan recognition by lectins and its repercussions in several fields, providing potential solutions for complex aspects that are emerging from different health challenges.

Integrin Structure

2000 ◽  
Vol 28 (4) ◽  
pp. 311-340 ◽  
Author(s):  
M.J. Humphries
Keyword(s):  
Cell Fate ◽  
Molecular Basis ◽  
Tertiary Structure ◽  
Cellular Migration ◽  
Model Studies ◽  
Physical Support ◽  
Tissue Organization ◽  
Wide Range ◽  
Ligand Interactions ◽  
Almost All

The integrins are a family of α,β heterodimeric receptors that mediate dynamic linkages between extracellular adhesion molecules and the intracellular actin cytoskeleton. Integrins are expressed by all multicellular animals, but their diversity varies widely among species; for example, in mammals, 19 α and 8β subunit genes encode polypeptides that combine to form 25 different receptors, whereas the Drosophila and Caenorhabditis genomes encode only five and two integrin a subunits respectively. Thousands of studies over the last two decades have investigated the molecular, cellular and organismal basis of integrin function. Gene deletion has demonstrated essential roles for almost all integrins, with the defects suggesting widespread contributions to both the maintenance of tissue integrity and the promotion of cellular migration. Integrin-ligand interactions are now considered to provide physical support for cells in order to maintain cohesion, to permit the generation of traction forces to enable movement, and to organize signalling complexes to modulate differentiation and cell fate. Animal-model studies have also shown that integrins contribute to the progression of many common diseases, and have implicated them as potential therapeutic targets. The use of anti-integrin monoclonal antibodies and ligand-mimetic peptides has validated this suggestion for inflammatory, neoplastic, traumatic and infectious conditions. Thus, to understand more about the mechanisms underlying tissue organization and cellular trafficking, and to identify approaches for regulating these processes in disease, there is intense interest in determining the molecular basis of integrin function. It is important to state at the outset that the tertiary structure of the integrin dimer is unknown. Our current understanding of the molecular basis of integrin function is therefore compiled from the results of a large number of studies that have employed a wide range of complementary technologies.

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