Unique mutational changes in SARS-CoV2 genome of different state of India (preprint)

COVID-19 is a global pandemic causing more than 8 million deaths till mid-August, 2020. In India, more than 3 million confirmed cases have been reported although with relatively low death rate of 1.8%. In this study, we sequenced 47 genomes of SARS-CoV-2 from the patients of 13 districts of Uttar Pradesh (UP), the largest state of India using third-generation sequencing technique. The phylogenetic clustering revealed that no UP sample was aligned with the previously defined USA clade, where the mortality was high. We identified 56 distinct SNP variations in the genomes of UP resulting in a unique mutation rate of 1.19% per sequence, which is greater than the value 0.88% obtained for the rest of India. The relatively less death rate in UP indicates that the mutation in the virus is deleterious. Further investigation is required with larger sample size to determine the degree of virulence vis-a-vis SNP variation.

SARS-CoV-2 3CLpro Whole Human Proteome Cleavage Prediction and Enrichment/Depletion Analysis (preprint)

A novel coronavirus (SARS-CoV-2) has devastated the globe as a pandemic that has killed more than 800,000 people. Effective and widespread vaccination is still uncertain, so many scientific efforts have been directed towards discovering antiviral treatments. Many drugs are being investigated to inhibit the coronavirus main protease, 3CLpro, from cleaving its viral polyprotein, but few publications have addressed this proteases interactions with the host proteome or their probable contribution to virulence. Too few host protein cleavages have been experimentally verified to fully understand 3CLpros global effects on relevant cellular pathways and tissues. Here, we set out to determine this proteases targets and corresponding potential drug targets. Using a neural network trained on coronavirus proteomes with a Matthews correlation coefficient of 0.983, we predict that a large proportion of the human proteome is vulnerable to 3CLpro, with 4,460 out of approximately 20,000 human proteins containing at least one predicted cleavage site. These cleavages are nonrandomly distributed and are enriched in the epithelium along the respiratory tract, brain, testis, plasma, and immune tissues and depleted in olfactory and gustatory receptors despite the prevalence of anosmia and ageusia in COVID-19 patients. Affected cellular pathways include cytoskeleton/motor/cell adhesion proteins, nuclear condensation and other epigenetics, host transcription and RNAi, coagulation, pattern recognition receptors, growth factor, lipoproteins, redox, ubiquitination, and apoptosis. This whole proteome cleavage prediction demonstrates the importance of 3CLpro in expected and nontrivial pathways affecting virulence, lead us to propose more than a dozen potential therapeutic targets against coronaviruses, and should therefore be applied to all viral proteases and experimentally verified.

Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies (preprint)

The global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein (SIP) network, based on disease signatures defined by COVID-19 multi-omic datasets(Bojkova et al., 2020; Gordon et al., 2020), and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials(Clinicaltrials.gov, 2020) testifying to the validity of the approach. Using artificial neural network analysis we classified these 200 drugs into 9 distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (130) and immune response (70). A subset of drugs implicated in viral replication were tested in cellular assays and two (proguanil and sulfasalazine) were shown to inhibit replication. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.

Experimental infection of cattle with SARS-CoV-2 (preprint)

Six cattle (Bos taurus) were intranasally inoculated with SARS-CoV-2 and kept together with three naive in-contact animals. Low-level virus replication and a specific sero-reactivity were observed in two inoculated animals, despite the presence of high antibody titers against a bovine betacoronavirus. The in-contact animals did not become infected.