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The current coronavirus pandemic, COVID-19, is the third outbreak of disease caused by the coronavirus family, after Severe Acute Respiratory Syndrome and Middle East Respiratory ...Syndrome. It is an acute infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This severe disease is characterised by acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. Currently, no drugs or vaccines exist against the disease and the only course of treatment is symptom management involving mechanical ventilation, immune suppressants, and repurposed drugs. The severe form of the disease has a relatively high mortality rate. The last six months have seen an explosion of information related to the host receptors, virus transmission, virus structure-function relationships, pathophysiology, co-morbidities, immune response, treatment and the most promising vaccines. This review takes a critically comprehensive look at various aspects of the host-pathogen interaction in COVID-19. We examine the genomic aspects of SARS-CoV-2, modulation of innate and adaptive immunity, complement-triggered microangiopathy, and host transmission modalities. We also examine its pathophysiological impact during pregnancy, in addition to emphasizing various gaps in our knowledge. The lessons learnt from various clinical trials involving repurposed drugs have been summarised. We also highlight the rationale and likely success of the most promising vaccine candidates.
The outbreak of COVID-19 caused by SARS-CoV-2 has resulted in more than 50 million confirmed cases and over 1 million deaths worldwide as of November 2020. Currently, there are no effective ...antivirals approved by the Food and Drug Administration to contain this pandemic except the antiviral agent remdesivir. In addition, the trimeric spike protein on the viral surface is highly glycosylated and almost 200,000 variants with mutations at more than 1,000 positions in its 1,273 amino acid sequence were reported, posing a major challenge in the development of antibodies and vaccines. It is therefore urgently needed to have alternative and timely treatments for the disease. In this study, we used a cell-based infection assay to screen more than 3,000 agents used in humans and animals, including 2,855 small molecules and 190 traditional herbal medicines, and identified 15 active small molecules in concentrations ranging from 0.1 nM to 50 μM. Two enzymatic assays, along with molecular modeling, were then developed to confirm those targeting the virus 3CL protease and the RNA-dependent RNA polymerase. Several water extracts of herbal medicines were active in the cell-based assay and could be further developed as plant-derived anti-SARS-CoV-2 agents. Some of the active compounds identified in the screen were further tested in vivo, and it was found that mefloquine, nelfinavir, and extracts of
(RF3),
, and
were effective in a challenge study using hamsters as disease model.
The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to ...treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent
activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC
) was 0.47 μM, very similar to its EC
against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 μM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 μM AT-511 (698 ± 15 and 236 ± 14 μM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC
observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.
The development of the SARS-CoV-2 pandemic has prompted an extensive worldwide sequencing effort to characterise the geographical spread and molecular evolution of the virus. A point mutation in the ...spike protein, D614G, emerged as the virus spread from Asia into Europe and the USA, and has rapidly become the dominant form worldwide. Here we review how the D614G variant was identified and discuss recent evidence about the effect of the mutation on the characteristics of the virus, clinical outcome of infection and host immune response.
•Largest cohort of patients with COVID-19 and neurological symptoms who underwent LP.•In all 30 cases, RT-PCR for SARS-CoV-2 from CSF was negative.•CSF analysis findings, including WBC, were normal ...in most patients with COVID-19.•Neurological symptoms in COVID-19 seem to be caused mainly by indirect mechanism.
The Coronavirus disease 2019 (COVID-19) pandemic poses a great threat to global public health. The original wild-type strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has ...genetically evolved, and several variants of concern (VOC) have emerged. On 26 November 2021, a new variant named Omicron (B.1.1.529) was designated as the fifth VOC, revealing that SARS-CoV-2 has the potential to go beyond the available therapies. The high number of mutations harboured on the spike protein make Omicron highly transmissible, less responsive to several of the currently used drugs, as well as potentially able to escape immune protection elicited by both vaccines and previous infection. We reviewed the latest publication and the most recent available literature on the Omicron variant, enlightening both reasons for concern and high hopes for new therapeutic strategies.
The trimeric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S) is the sole viral protein responsible for both viral binding to a host cell and the membrane fusion event ...needed for cell entry. In addition to facilitating fusion needed for viral entry, S can also drive cell–cell fusion, a pathogenic effect observed in the lungs of SARS-CoV-2–infected patients. While several studies have investigated S requirements involved in viral particle entry, examination of S stability and factors involved in S cell–cell fusion remain limited. A furin cleavage site at the border between the S1 and S2 subunits (S1/S2) has been identified, along with putative cathepsin L and transmembrane serine protease 2 cleavage sites within S2. We demonstrate that S must be processed at the S1/S2 border in order to mediate cell–cell fusion and that mutations at potential cleavage sites within the S2 subunit alter S processing at the S1/S2 border, thus preventing cell–cell fusion. We also identify residues within the internal fusion peptide and the cytoplasmic tail that modulate S-mediated cell–cell fusion. In addition, we examined S stability and protein cleavage kinetics in a variety of mammalian cell lines, including a bat cell line related to the likely reservoir species for SARS-CoV-2, and provide evidence that proteolytic processing alters the stability of the S trimer. This work therefore offers insight into S stability, proteolytic processing, and factors that mediate S cell–cell fusion, all of which help give a more comprehensive understanding of this high-profile therapeutic target.
COVID-19 CG (covidcg.org) is an open resource for tracking SARS-CoV-2 single-nucleotide variations (SNVs), lineages, and clades using the virus genomes on the GISAID database while filtering by ...location, date, gene, and mutation of interest. COVID-19 CG provides significant time, labor, and cost-saving utility to projects on SARS-CoV-2 transmission, evolution, diagnostics, therapeutics, vaccines, and intervention tracking. Here, we describe case studies in which users can interrogate (1) SNVs in the SARS-CoV-2 spike receptor binding domain (RBD) across different geographical regions to inform the design and testing of therapeutics, (2) SNVs that may impact the sensitivity of commonly used diagnostic primers, and (3) the emergence of a dominant lineage harboring an S477N RBD mutation in Australia in 2020. To accelerate COVID-19 efforts, COVID-19 CG will be upgraded with new features for users to rapidly pinpoint mutations as the virus evolves throughout the pandemic and in response to therapeutic and public health interventions.
Surrogate neutralization assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be done without biosafety level 3 containment and in multiple species are desirable. We ...evaluate a recently developed surrogate virus neutralization test (sVNT) in comparison to 90% plaque reduction neutralization tests (PRNT
) in human, canine, cat, and hamster sera. With PRNT
as the reference, sVNT had sensitivity of 98.9% and specificity of 98.8%. Using a panel of immune sera corresponding to other coronaviruses, we confirm the lack of cross-reactivity to other coronaviruses in SARS-CoV-2 sVNT and PRNT
, except for cross-reactivity to SARS-CoV-1 in sVNT.
Testing is one of the commendable measures for curbing the spread of coronavirus disease (COVID‐19). But, it should be done using the most appropriate specimen and an accurate diagnostic test such as ...real‐time reverse transcription‐polymerase chain reaction (qRT‐PCR). Therefore, a systematic review was conducted to determine the positive detection rate of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in different clinical specimens using qRT‐PCR. A total of 8136 pooled clinical specimens were analyzed to detect SARS‐CoV‐2, the majority were nasopharyngeal swabs (69.6%). A lower respiratory tract (LRT) specimens had a positive rate (PR) of 71.3% (95% confidence interval CI: 60.3%‐82.3%) while no virus was detected in the urinogenital specimens. Bronchoalveolar lavage fluid (BLF) specimen had the PR of 91.8% (95% CI: 79.9%‐103.7%), followed by rectal swabs; 87.8% (95% CI: 78.6%‐96.9%) then sputum; 68.1% (95% CI: 56.9%‐79.4%). A low PR was observed in oropharyngeal swabs; 7.6% (95% CI: 5.7%‐9.6%) and blood samples; 1.0% (95% CI: −0.1%‐2.1%) whereas no SARS‐CoV‐2 was detected in urine samples. Feces had a PR of 32.8% (95% CI:1 5.8%‐49.8%). Nasopharyngeal swab, a widely used specimen had a PR of 45.5% (95% CI: 31.2%‐59.7%). In this study, SARS‐CoV‐2 was highly detected in LRT specimens while no virus was detected in urinogenital specimens. BLF had the highest PR followed by rectal swab then sputum. Nasopharyngeal swab which is widely used had moderate PR. Low PR was recorded in oropharyngeal swab and blood samples while no virus was found in urine samples. Last, the virus was detected in feces, suggesting SARS‐CoV‐2 transmission by the fecal route.
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