Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
1.
Preprint in English | Other preprints | ID: ppcovidwho-295462

ABSTRACT

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with Molecular Dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5’ UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in the stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel antiviral agents.

2.
Front Pharmacol ; 12: 660490, 2021.
Article in English | MEDLINE | ID: covidwho-1369702

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has caused a significant number of fatalities and worldwide disruption. To identify drugs to repurpose to treat SARS-CoV-2 infections, we established a screen to measure the dimerization of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the virus. This screen identified fenofibric acid, the active metabolite of fenofibrate. Fenofibric acid also destabilized the receptor-binding domain (RBD) of the viral spike protein and inhibited RBD binding to ACE2 in enzyme-linked immunosorbent assay (ELISA) and whole cell-binding assays. Fenofibrate and fenofibric acid were tested by two independent laboratories measuring infection of cultured Vero cells using two different SARS-CoV-2 isolates. In both settings at drug concentrations, which are clinically achievable, fenofibrate and fenofibric acid reduced viral infection by up to 70%. Together with its extensive history of clinical use and its relatively good safety profile, this study identifies fenofibrate as a potential therapeutic agent requiring an urgent clinical evaluation to treat SARS-CoV-2 infection.

3.
Adv Mater ; 33(26): e2008304, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1248674

ABSTRACT

Airborne pathogens pose high risks in terms of both contraction and transmission within the respiratory pathways, particularly the nasal region. However, there is little in the way of adequate intervention that can protect an individual or prevent further spread. This study reports on a nasal formulation with the capacity to combat such challenges, focusing on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Formulation of a polysaccharide-based spray, known for its mucoadhesive properties, is undertaken and it is characterized for its mechanical, spray distribution, and antiviral properties. The ability to engineer key mechanical characteristics such as dynamic yield stresses and high coverage is shown, through systematic understanding of the composite mixture containing both gellan and λ-carrageenan. Furthermore, the spray systems demonstrate highly potent capacities to prevent SARS-CoV-2 infection in Vero cells, resulting in complete inhibition when either treating, the cells, or the virus, prior to challenging for infection. From this data, a mechanism for both prophylaxis and prevention is proposed; where entrapment within a polymeric coating sterically blocks virus uptake into the cells, inactivating the virus, and allowing clearance within the viscous medium. As such, a fully preventative spray is formulated, targeted at protecting the lining of the upper respiratory pathways against SARS-CoV-2.


Subject(s)
Drug Compounding , Nasal Sprays , Polymers/chemistry , SARS-CoV-2/physiology , Animals , COVID-19/pathology , COVID-19/virology , Carrageenan/chemistry , Chlorocebus aethiops , Humans , Polymers/pharmacology , Polysaccharides, Bacterial/chemistry , SARS-CoV-2/isolation & purification , Vero Cells , Virus Internalization/drug effects
4.
BMJ Paediatr Open ; 5(1): e001063, 2021.
Article in English | MEDLINE | ID: covidwho-1244898

ABSTRACT

The devastating impact of the COVID-19 pandemic on global health and economic stability is immeasurable. The situation is dynamic and fast-evolving, with the world facing new variants of concern which may have immune escape potential. With threatened treatment and preventative strategies at stake, and the prospect of reinfection prolonging the pandemic, it is more crucial than ever to understand the pathogenesis of SARS-CoV-2 infection, which intriguingly disproportionately affects adults and the elderly. Children infected with SARS-CoV-2 remain largely asymptomatic or undergo a transient mild illness. Understanding why children have a milder phenotype and a significant survival advantage may help identify modifiable risk factors in adults. Current evidence suggests adults with COVID-19 show variability in innate and adaptive immune responses, which result in uncontrolled proinflammatory cytokine production in some patients, leading to severe disease and mortality. Children with acute COVID-19 infection seldom progress to acute respiratory distress syndrome and are less likely to exhibit the cytokine storm which is so prominent in adults. Even with the Kawasaki-like illness, a hyperinflammation syndrome also known as paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2, mortality is low. The key to successfully combating SARS-CoV-2 and future zoonotic pandemics may lie in understanding these critical differences and merits focused consideration and research. The impact of community transmission among asymptomatic children is unknown; sustained global decline in infection rates and control of the COVID-19 pandemic may not be achieved until vaccination of children occurs. In this review, we discuss the fundamental differences in the immune response between children and adults in the fight against SARS-CoV-2.

5.
Angew Chem Int Ed Engl ; 60(33): 18144-18151, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1206743

ABSTRACT

The untranslated regions (UTRs) of viral genomes contain a variety of conserved yet dynamic structures crucial for viral replication, providing drug targets for the development of broad spectrum anti-virals. We combine in vitro RNA analysis with molecular dynamics simulations to build the first 3D models of the structure and dynamics of key regions of the 5' UTR of the SARS-CoV-2 genome. Furthermore, we determine the binding of metallo-supramolecular helicates (cylinders) to this RNA structure. These nano-size agents are uniquely able to thread through RNA junctions and we identify their binding to a 3-base bulge and the central cross 4-way junction located in stem loop 5. Finally, we show these RNA-binding cylinders suppress SARS-CoV-2 replication, highlighting their potential as novel anti-viral agents.


Subject(s)
5' Untranslated Regions , Antiviral Agents/pharmacology , Macromolecular Substances/pharmacology , RNA/metabolism , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Chlorocebus aethiops , Coordination Complexes/chemistry , Coordination Complexes/metabolism , Coordination Complexes/pharmacology , Genome, Viral/drug effects , Macromolecular Substances/chemistry , Macromolecular Substances/metabolism , Metals, Heavy/chemistry , Molecular Dynamics Simulation , RNA/genetics , SARS-CoV-2/chemistry , Vero Cells
7.
Nat Rev Gastroenterol Hepatol ; 18(5): 348-364, 2021 05.
Article in English | MEDLINE | ID: covidwho-1127158

ABSTRACT

Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity.


Subject(s)
COVID-19/epidemiology , Liver Diseases/epidemiology , Pandemics , Comorbidity , Disease Progression , Humans , SARS-CoV-2
9.
Cardiovasc Res ; 116(14): 2177-2184, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-693970

ABSTRACT

The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.


Subject(s)
COVID-19/virology , Cardiovascular Diseases/virology , Endothelium, Vascular/virology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/physiopathology , Cardiovascular Agents/therapeutic use , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/physiopathology , Cytokines/metabolism , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Endothelium, Vascular/physiopathology , Host-Pathogen Interactions , Humans , Inflammation Mediators/metabolism , Prognosis , Risk Assessment , Risk Factors , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Virus Internalization
SELECTION OF CITATIONS
SEARCH DETAIL
...