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1.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.11.23.20235002

ABSTRACT

Fine scale delineation of epitopes recognized by the antibody response to SARS-CoV-2 infection will be critical to understanding disease heterogeneity and informing development of safe and effective vaccines and therapeutics. The Serum Epitope Repertoire Analysis (SERA) platform leverages a high diversity random bacterial display library to identify epitope binding specificities with single amino acid resolution. We applied SERA broadly, across human, viral and viral strain proteomes in multiple cohorts with a wide range of outcomes from SARS-CoV-2 infection. We identify dominant epitope motifs and profiles which effectively classify COVID-19, distinguish mild from severe disease, and relate to neutralization activity. We identify a repertoire of epitopes shared by SARS-CoV-2 and endemic human coronaviruses and determine that a region of amino acid sequence identity shared by the SARS-CoV-2 furin cleavage site and the host protein ENaC-alpha is a potential cross-reactive epitope. Finally, we observe decreased epitope signal for mutant strains which points to reduced antibody response to mutant SARS-CoV-2. Together, these findings indicate that SERA enables high resolution of antibody epitopes that can inform data-driven design and target selection for COVID-19 diagnostics, therapeutics and vaccines.


Subject(s)
COVID-19
2.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.11.25.399055

ABSTRACT

Background: An immediate unmet medical need exists to test and develop existing approved drugs against SARS-COV-2. Despite many efforts, very little progress has been made regarding finding low-cost oral medicines that can be made widely available worldwide to address the global pandemic. Methods: We sought to examine if a triple combination of nitazoxanide (using its active metabolite tizoxanide), ribavirin, and hydroxychloroquine would lead to a multiplicative effects on viral replication of SARS-COV-2 resulting in a significant reduction of virus yield using VERO E6 cells as a model of viral replication. Results: Virus yield measured in PFU/ml was ~ 2 logs lower with triple combination versus either drug alone, resulting in the prolongation of time to peak cytopathic effects (CPE). The time to produce 50% CPE increased from 2.8 days for viral controls versus 5.3 days for triple combination therapy. Finally, for each 1-log reduction in virus yield 24 hours post-infection, there was an additional 0.7-day delay in onset of CPE. Conclusions: A triple combination of tizoxanide, ribavirin, and hydroxychloroquine produced a reduction in SARS-COV-2 viral replication in Vero E6 cells, warranting exploration in additional cell lines as well as human clinical trials.

3.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.241349

ABSTRACT

While transcriptome- and proteome-wide technologies to assess processes in protein biogenesis are now widely available, we still lack global approaches to assay post-ribosomal biogenesis events, in particular those occurring in the eukaryotic secretory system. We here developed a method, SECRiFY, to simultaneously assess the secretability of >105 protein fragments by two yeast species, S. cerevisiae and P. pastoris, using custom fragment libraries, surface display and a sequencing-based readout. Screening human proteome fragments with a median size of 50 - 100 amino acids, we generated datasets that enable datamining into protein features underlying secretability, revealing a striking role for intrinsic disorder and chain flexibility. SECRiFY is the first methodology that generates sufficient amounts of annotated data for advanced machine learning methods to deduce secretability predictors. The finding that secretability is indeed a learnable feature of protein sequences is of significant impact in the broad area of recombinant protein expression and de novo protein design.


Subject(s)
Sleep Disorders, Intrinsic
4.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.11.25.398859

ABSTRACT

The emergence of SARS-CoV-2 virus has resulted in a worldwide pandemic, but an effective antiviral therapy has yet to be discovered. To improve treatment options, we conducted a high-throughput drug repurposing screen to uncover compounds that block the viral activity of SARS-CoV-2. A minimally pathogenic human betacoronavirus (OC43) was used to infect physiologically-relevant human pulmonary fibroblasts (MRC5) to facilitate rapid antiviral discovery in a preclinical model. Comprehensive profiling was conducted on more than 600 compounds, with each compound arrayed at 10 dose points (ranging from 20 M to 1 nM). Our screening revealed several FDA-approved agents that act as novel antivirals that block both OC43 and SARS-CoV-2 viral replication, including lapatinib, doramapimod, and 17-AAG. Importantly, lapatinib inhibited SARS-CoV-2 replication by over 50,000-fold without any toxicity and at doses readily achievable in human tissues. Further, both lapatinib and doramapimod could be combined with remdesivir to dramatically improve antiviral activity in cells. These findings reveal novel treatment options for people infected with SARS-CoV-2 that can be readily implemented during the pandemic.


Subject(s)
Drug-Related Side Effects and Adverse Reactions , Hallucinations
5.
medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.10.19.20215368

ABSTRACT

ABSTRACT Despite the high level of morbidity and mortality worldwide, there is increasing evidence for asymptomatic carriers of the novel coronavirus SARS-CoV-2. We analyzed blood specimens from 1,559 healthy blood donors, collected in the greater New York metropolitan area between the months of March and July 2020 for antibodies to SARS-CoV-2 virus. Using our proprietary technology, SERA (Serum Epitope Repertoire Analysis), we observed a significant increase in SARS-CoV-2 seropositivity rates over the four-month period, from 0% [95% CI: 0 - 1.5%] (March) to 11.6% [6.0 - 21.2%] (July). Follow-up ELISA tests using S1 and nucleocapsid viral proteins confirmed most of these results. Our findings are consistent with seroprevalence studies within the region and with reports that SARS-COV-2 infections can be asymptomatic or cause only mild symptoms. IMPORTANCE The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has caused vast morbidity and mortality worldwide, yet several studies indicate that there may be a significant number of infected people who are asymptomatic or exhibit mild symptoms. In this study, samples were collected from healthy blood donors in a region of rapidly increasing disease burden (New York metropolitan area) and we hypothesized that a subset would be seropositive to SARS-CoV-2. People who experienced mild or no symptoms during SARS-CoV-2 infection may represent a source for convalescent plasma donors.


Subject(s)
COVID-19 , Severe Acute Respiratory Syndrome , Hallucinations
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