Vulnerabilities of the SARS-CoV-2 virus to proteotoxicity – opportunity for repurposed chemotherapy of COVID-19 infection

Abstract

bioRxiv preprint which are glycated to hydroimidazolone MG-H1 with loss of charge, all related electrostatic interactions and, typically, resistance to proteolytic cleavage close to the site of modification ( Figure 1B) (Rabbani et al., 2016b).Key to exploring if reactive metabolites of the host may be exploited to produce a virucidal response against SARS-CoV-2 is to identify proteomic vulnerabilities of the virus.Currently it is unknown if target amino acid residues of reactive metabolites are enriched in functional domains of the viral proteome, and if these targets are enriched in the viral proteome, compared to the human host. It also unknown if there are investigational new drugs or current clinically approved drugs that increase reactive metabolites to virucidal levels in the cellular environment where SARS-CoV-2 undergo cell fusion and propagation.To address this knowledge gap, we initiated a series of studies using protein informatics tools, available proteomics data and a cell model used in SARS-CoV-2 fusion and propagation. Herein we report the susceptibility of the SARS-CoV-2 virus to increased MG or "dicarbonyl stress" (Rabbani et al., 2016b) based on enrichment of arginine residues in functional domains and enrichment of amino acid motif MG modification sites in the SARS-CoV-2 proteome, and two clinically approved antitumor drugs that increase the cellular concentration of MG to virucidal levels. We propose these drugs be considered for repurposing for treatment of COVID-19 disease. RESULTS Enrichment of arginine residues in the functional domains in the SARS-CoV-2 proteome.We acquired the reference sequences of the 29 proteins of the SARS-CoV-2 proteome (Table S1) and also, for reference, 18,821 reviewed protein sequences of human host proteins from was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site

“…Additionally, the 'up' and 'down' conformations of RBD domain observed during MD simulations, supports that concept that the S protein can also be a target of a possible IgG therapeutic [91]. From the list of the top compounds identified that dock into the trimer cavity, some of them have already been validated as SARS-CoV-2 virus inhibitors in cells, including; a Chitosan derivative [53][54][55], Rapamycin [47][48][49], Everolimus (RAD001) [49], Paclitaxal [78], Ritonavir [48,[50][51][52], SelaMeerin (Selamectin) [79], and Danoprevir [52]. Among these, a modified polymeric version of the Chitosan drug (a top hit in our analysis) was recently shown to inhibit CoV replication with evidence that the molecule inhibits the binding of the viral S protein to the host ACE2 receptor [53][54][55].…”

“…The compounds that exhibit a relatively high binding affinity towards the SARS-CoV-2 spike glycoprotein trimer cavity with a binding affinity -35 to -71 kcal/mol (GBVI/WSA dG) towards the trimer cavity of the S protein recorded. From the list of ligands showing best binding, the compounds that were already proven or suggested to be / can be active against the SARS-CoV-2 virus includes (Table 1): Chitosan [53][54][55], Rapamycin [47][48][49], Everolimus (RAD001) [49], Paclitaxal [78], Ritonavir [48,[50][51][52], SelaMeerin (Selamectin) [79], and danoprevir [52].…”

“…By docking of known drugs within the trimer cavity of S protein, the relative selectivity of the cavity suggests that the majority of drugs will have a molecular weight ≥ ~700 g/mol will show better binding affinity. Particularly, a specific class of ligands (mostly macrolide type) were found showing better fitting to the trimer cavity (Figure 4a), for example, Rapamycin [47][48][49], Everolimus (RAD001) [49], Paclitaxal [78], and SelaMeerin (Selamectin) [79] (Figure 4a). The intermolecular interactions between the S protein and compounds, suggests that residues from all three chains (A, B, and C) forming the trimer cavity are actively involved in binding with the drugs.…”

Lab-on-a-Chip Technologies for the Single Cell Level: Separation, Analysis, and Diagnostics

“…With careful sample treatment, -omics can be very well used for diagnostic chips and to unravel to exact roles of individual substances within these cells, their metabolism, their transcription during cell division, or all of the above. Proteomics has been massively employed to elucidate the host interactions of SARS-CoV-2, the causative agent of COVID-19 [27][28][29][30][31][32], the greatest pandemic in our millennium.…”

“…One very prominent aspect of microfluidic research is diagnostics on the single-cell or even molecular level. The significance of recent research towards microfluidics-based single cell diagnostic chips is apparent in health care, in our homes, and also very prominently in the fight against the COVID 19 pandemic: The diagnostic targets range from circulating tumor cells (CTC) [1][2][3][4][5][6], over parasites in blood [7][8][9][10][11][12][13][14][15], male fertility [16][17][18][19][20], molecular markers for infections [11,15,[21][22][23], cells of a specific stage in their life cycle [24,25], plant pathogens [26] and the SARS-CoV-2 proteome [27][28][29][30][31][32]. Depending on the exact target (either the entire cell or sub-cellular markers) there are different approaches to on-chip detection, each with their own underlying fundamentals and set of limitations.…”