Mclamblindhardt6957

Containment of the COVID-19 pandemic requires reducing viral transmission. SARS-CoV-2 infection is initiated by membrane fusion between the viral and host cell membranes, mediated by the viral spike protein. We have designed a dimeric lipopeptide fusion inhibitor that blocks this critical first step of infection for emerging coronaviruses and document that it completely prevents SARS-CoV-2 infection in ferrets. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and non-toxic and thus readily translate into a safe and effective intranasal prophylactic approach to reduce transmission of SARS-CoV-2.

A dimeric form of a SARS-CoV-2-derived lipopeptide is a potent inhibitor of fusion and infection

and transmission

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A dimeric form of a SARS-CoV-2-derived lipopeptide is a potent inhibitor of fusion and infection in vitro and transmission in vivo .There is an urgent need for an accessible and low-cost COVID-19 vaccine suitable for low- and middle-income countries. Here we report on the development of a SARS-CoV-2 receptor-binding domain (RBD) protein, expressed at high levels in yeast ( Pichia pastoris ), as a suitable vaccine candidate against COVID-19. After introducing two modifications into the wild-type RBD gene to reduce yeast-derived hyperglycosylation and improve stability during protein expression, we show that the recombinant protein, RBD219-N1C1, is equivalent to the wild-type RBD recombinant protein (RBD219-WT) in an in vitro ACE-2 binding assay. Immunogenicity studies of RBD219-N1C1 and RBD219-WT proteins formulated with Alhydrogel ® were conducted in mice, and, after two doses, both the RBD219-WT and RBD219-N1C1 vaccines induced high levels of binding IgG antibodies. Using a SARS-CoV-2 pseudovirus, we further showed that sera obtained after a two-dose immunization schedule of the vaccines were sufficient to elicit strong neutralizing antibody titers in the 11,000 to 110,000 range, for both antigens tested. The vaccines induced IFN-γ, IL-6, and IL-10 secretion, among other cytokines. Overall, these data suggest that the RBD219-N1C1 recombinant protein, produced in yeast, is suitable for further evaluation as a human COVID-19 vaccine, in particular, in an Alhydrogel ® containing formulation and possibly in combination with other immunostimulants.

In the event of an outbreak due to an emerging pathogen, time is of the essence to contain or to mitigate the spread of the disease. Drug repositioning is one of the strategies that has the potential to deliver therapeutics relatively quickly. The SARS-CoV-2 pandemic has shown that integrating critical data resources to drive drug-repositioning studies, involving host-host, hostpathogen and drug-target interactions, remains a time-consuming effort that translates to a delay in the development and delivery of a life-saving therapy.

Here, we describe a workflow we designed for a semi-automated integration of rapidly emerging datasets that can be generally adopted in a broad network pharmacology research setting. The workflow was used to construct a COVID-19 focused multimodal network that integrates 487 host-pathogen, 74,805 host-host protein and 1,265 drug-target interactions. The resultant Neo4j graph database named "Neo4COVID19" is accessible via a web interface and via API calls based on the Bolt protocol. We believe that our Neo4COVID19 database will be a valuable asset to the research community and will catalyze the discovery of therapeutics to fight COVID-19.

https//neo4covid19.ncats.io.

https//neo4covid19.ncats.io.SARS-CoV-2, a betacoronavirus with a positive-sense RNA genome, has caused the ongoing COVID-19 pandemic. Although a large number of transcriptional profiling studies have been conducted in SARS-CoV-2 infected cells, little is known regarding the translational landscape of host and viral proteins. Here, using ribosome profiling in SARS-CoV-2-infected cells, we identify structural elements that regulate viral gene expression, alternative translation initiation events, as well as host responses regulated by mRNA translation. Caspase inhibitor We found that the ribosome density was low within the SARS-CoV-2 frameshifting element but high immediately downstream, which suggests the utilization of a highly efficient ribosomal frameshifting strategy. In SARS-CoV-2-infected cells, although many chemokine, cytokine and interferon stimulated genes were upregulated at the mRNA level, they were not translated efficiently, suggesting a translational block that disarms host innate host responses. Together, these data reveal the key role of mRNA translation in SARS-CoV-2 replication and highlight unique mechanisms for therapeutic development.

Ribo-seq reveals key translationally regulated events in SARS-CoV-2 replicationSARS-CoV-2 frameshifting is substantially more efficient than HIV-1SARS-CoV-2 infection results in transcriptional upregulation of inflammatory and interferon-stimulated genesSARS-CoV-2 disarms host responses at the level of mRNA translation.

Ribo-seq reveals key translationally regulated events in SARS-CoV-2 replicationSARS-CoV-2 frameshifting is substantially more efficient than HIV-1SARS-CoV-2 infection results in transcriptional upregulation of inflammatory and interferon-stimulated genesSARS-CoV-2 disarms host responses at the level of mRNA translation.Epidemiological studies suggest that men exhibit a higher mortality rate to COVID-19 than women, yet the underlying biology is largely unknown. Here, we seek to delineate sex differences in the expression of entry genes ACE2 and TMPRSS2 , host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment. Using over 220,000 human gene expression profiles covering a wide range of age, tissues, and diseases, we found that male samples show higher expression levels of ACE2 and TMPRSS2 , especially in the older group (>60 years) and in the kidney. Analysis of 6,031 COVID-19 patients at Mount Sinai Health System revealed that men have significantly higher creatinine levels, an indicator of impaired kidney function. Further analysis of 782 COVID-19 patient gene expression profiles taken from upper airway and blood suggested men and women present profound expression differences in responses to SARS-CoV-2. Computational deconvolution analysis of these profiles revealed male COVID-19 patients have enriched kidney-specific mesangial cells in blood compared to healthy patients.