SARS-CoV-2 3CLpro whole human proteome cleavage prediction and enrichment/depletion analysis

Abstract

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 protease's interactions with the host proteome or their probable contribution to virulence. Too few host protein cleavages have been experimentally verified to fully understand 3CLpro's global effects on relevant cellular pathways and tissues. Here, we set out to determine this protease's 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.

JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy

“…The PL pro also houses de-ubiquitination and de- ISGylation properties via the JAK-STAT pathway. Specifically, it is known to cleave STAT2 and affect the interferon signaling [ 31 , 75 ]. Among the structural proteins of SARS-CoV-2, the N protein has also been shown to inhibit the type 1 IFN pathway mediated inflammatory cascade by preventing the phosphorylation and nuclear passage of STAT 1 and STAT 2 as shown in Figure 3 [ 76 ].…”

Fast and accurate genome-wide predictions and structural modeling of protein-protein interactions using Galaxy

“…The two highest ranking interactions were identified for ISG15 (SM-score=1.11) and ANKUB (SM-score=1.10). ISG15 has recently been experimentally confirmed as a substrate (Shin, 2020) and ANKUB was suggested in a computational cleavage enrichment study (Prescott, 2020).…”

Alphavirus nsP2 protease structure and cleavage prediction: Possible relevance to the pathogenesis of viral arthritis

“…As in my previous work on 3CLpro and PLpro,[14, 15] sequence logo-based logistic regression and naïve Bayes classification and physiochemical and one-hot encoded neural networks (NNs) were used for cleavage prediction. [28] To reduce any potential false positives, only proteins expressed in relevant cell types with cleavages with agreement between all five NN replicates and with total solvent-accessible surface areas (SASAs) of more than 100 Å 2 between positions P5 and P5’ were reported.…”

“…Due to the few cleavages per polyprotein and the continually expanding taxonomy of alphaviruses, few viral proteases or their cleavages have been characterized. [13] Following the successful application of machine learning methods to other viral proteases for cleavage prediction in human proteins,[14–16] computational analysis of alphavirus proteases will likely be an important step toward discovering additional therapeutic targets.…”