PMC:7544934 / 12929-24062 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7544934","sourcedb":"PMC","sourceid":"7544934","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7544934","text":"Results\n\nLDN treatment diminishes LPS induced cytokine storm\nCytokine storm is a very commonly observed factor in most severe COVID-19 patients and also one of the leading causes of mortality (Coperchini et al., 2020; Rahmati and Moosavi, 2020; Zhang et al., 2020). Peripheral blood of severe COVID-19 patients has also shown a high level of cytokine storm (Wu and Yang, 2020). Keeping in mind the ability of lipopolysaccharide (LPS) to cause sepsis and triggers an uncontrolled systemic inflammatory response in murine macrophage cells (Ramos-Benitez et al., 2018), we treated macrophage cells with LPS (1 µg/ml) in the presence and absence of LDN (5 µM). The dose of LDN chosen is non-toxic (Figure S2) as found in cell viability using MTT (4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide) assay following the standard protocol (Dogra et al., 2019).\nResults demonstrated that LPS treatment significantly induced expression on pro-inflammatory cytokines (IL-1β, IL-6 and mcp-1) whereas, LDN significantly inhibited LPS expression of IL-1β, IL-6 and mcp-1 in macrophage cells (Figure 1(A)). Next, we tested the possible involvement of LPS in inducing the release of pro-inflammatory cytokines, and we also determine the effects of LDN on release of pro-inflammatory mediators in LPS induced macrophage cells (Figure 1(B)). Conditioned media from LPS challenged macrophage cells showed a significantly enhanced release pro-inflammatory mediators (IL-1β, MCP-1 and IL-6) and interestingly we found that LDN treatment attenuated LPS induced IL-1β, MCP1 and IL-6 level (Figure 1(B)). These data suggest that LPS induced macrophage cells, to release - pro-inflammatory mediators, and LDN treatment can significantly abrogate LPS induced release of pro-inflammatory mediators in media. Adipose tissue macrophages (ATMs) is closely linked to this inflammatory condition which leads to numbers of diseases and the ability of High Fat Diet (HFD) feeding on increased LPS uptake and trafficking to macrophages and other targets are well known (Hersoug et al., 2016). Hence in this study, we investigated the effect of HFD on proinflammatory markers expression in purified ATMs. Expression of pro-inflammatory markers such as IL-1β, MCP-1 and IL-6 was induced (Figure 1(C)) whereas LDN attenuates HFD induced pro-inflammatory cytokines expression. Altogether, this data clearly shows that LDN treatment may protect (by reducing elevated M1 cytokines) against inflammation.\nFigure 1. (A) LDN prevents LPS induced pro-inflammatory cytokines expression and release Quantitative mRNA expression of indicated genes (mcp-1, il-6 and Il1b) in murine macrophage cells. (B) ELISA of pro-inflammatory proteins (MCP-1, IL-6 and IL-1β) in conditioned media from LPS challenged murine macrophage cells in the present and absence of LDN (C) Quantitative mRNA expression of IL-1β, mcp-1 and IL-6 in purified ATMs from all group mice. Values are expressed as mean ± SEM (n = 3) from three independent sets of repeats (mean ± SEM ***p \u003c 0.001, **p, ^^p \u003c 0.01 *p,^p \u003c 0.05.) (D) LDN acts as EKR1 inhibitor and improved insulin sensitivity in LPS treated macrophage cells. ERK1/2 (Immunoblot) in RAW cells treated with LPS (1ug/ml) in the presence and absence of LDN.\n\nLDN treatment attenuates LPS induced ERK1/2 phosphorylation\nERK1 and ERK2 mitogen-activated protein kinases (MAPK) play a critical role in the regulation of cell proliferation and differentiation in response to mitogens and other extracellular stimuli. Mitogens and cytokines that activate MAPK in cells have been shown to activate virus replication (Cai et al., 2007). The cytokine storm is a well-known factor that is increasing the severity and mortality in COVID19 (Coperchini et al., 2020; Rahmati and Moosavi, 2020; Zhang et al., 2020). Moreover, the phosphorylation status of ERK1/2 is positively correlated with virus load and reduced ERK1/2 phosphorylation suppressed viral replication significantly, thus reduced viral load (Cai et al., 2007). We pre-treated the cells with LDN and were exposed to LPS for 18 h. As shown in Figure 1(D), the phosphorylation of ERK 1/2 was increased after LPS exposure which was significantly suppressed by LDN treatment (Figure 1(D)). This finding suggests that LDN can acts as an inhibitor for ERK1/2 activation and may reduce the infectivity of virions.\n\nIn-silico studies revealed LDN interacts with the receptor-binding motif of SARS-CoV-2-RBD\nThe latest research shows that the spike-receptor binding domain (RBD) sequence of SARS-CoV-2 interacts with host receptor ACE2 and this RBD-ACE2 complex plays a key role in virus invasion and virulence. Based on the current research progress, the RBD-ACE2 complex is considered as a target for the treatment of coronavirus infection to block SARS-CoV-2 from entering host cells.\nTo understand the mode of interaction naltrexone in the binding interface of RBD-ACE2 complex, molecular docking was performed using AutoDock. The docking scores of the top ten complexes have been summarized in Table S1. As evidenced by the top-ranked conformation (as shown in Figure 2), the naltrexone prefers to bind in the cavity formed RBD and ACE2 receptor. Tyr505 and Glu406 of RBD formed two crucial hydrogen bonds with the naltrexone with an atomic distance of 2.08 and 1.80, while, Arg403 formed electrostatic contact. While the His34, Glu37, and Phe390 of ACE2 displayed several hydrophobic contacts (mostly pi-alkyl contacts) with naltrexone.\nFigure 2. The docked conformation of naltrexone at the binding interface of RBD-ACE2 complex obtained from AutoDock (A) and interface amino acid residues involved in non-bonded contacts are labelled (B). The residues labeled in blue represent RBD and in pink are ACE2. Further, we compared ACE2-RBD/Naltrexone binding affinity with some recently reported potential ACE2-RBD inhibitors. Both (SSAA09E2 and Bisoctrizole) displayed an affinity score of −6.7 kcal/mol and −8.5 kcal/mol respectively with the ACE2-RBD complex as compared to Naltrexone which shows an affinity score of −6.01 kcal mol−1 (Figure S3). Comparative analysis of docked conformation of two reported inhibitors as compared to Naltrexone revealed that the former two prefers to occupy the inner central cavity in ACE2-RBD complex (close to the N-terminus contact interface) and while Naltrexone occupied the core central surface with a greater number of contacts with the RBD of SARS Cov-2. As Naltrexone occupies the central interface of ACE2-RBD complex, thus, it can be expected to break a greater number of crucial contacts which in turn can inhibit the binding of RBD to host receptor ACE2. Further in-vitro and in-vivo studies are required to understand the efficacy of these compounds to understand the molecular basis of anti-coronavirus activity or inhibitory potential.\nFigure 3. Dynamics stability of RBD-ACE2-Naltrexone complex during 100 ns molecular dynamics simulation. (A) The root-mean square deviation (RMSD) of RBD-ACE2-Naltrexone complex during 100 ns MD in aqueous solution. (B) The compactness of the measured by the radius of gyration profile of complex with respect to time (C) The Cα-root mean squared fluctuation profile of the ACE2 and RBD during MD.\n\nTrajectory analysis\nThe dynamics stability of the RBD-ACE2-naltrexone complex was analyzed by performing all-atoms MD simulations of 100 ns in GROMACS. The backbone RMSD analysis provides important information on the stability of protein and protein-ligand complexes and the time when simulation reached equilibrium. The RMSD of the RBD-ACE2-naltrexone complex displayed an average RMSD ∼2.46 Å throughout the entire simulation (Figure 3(A)). Besides, the RMSD of ligand was also found to be stable (red line in Figure 3(A)) with very minimal deviation as compared to the starting conformation. Overall, the complex system displayed the least backbone deviation, indicates that docked conformation is accurate and remained stable over the 100 ns timescale. Radiuses of gyration assess the compactness of the system, where a compact gyradius of ∼3.24 nm for the complex indicates the consistent shape and size of the system during the simulation (Figure 3(B)). The residue flexibility of protease and RBD-ACE2/Naltrexone complex was examined by performing Cα RMSF analysis of both the sub-units (Figure 3(C)). The average RMSF of ACE2 was found to be 0.14 nm, while for the RBD it was reported to be 0.17 nm (for the receptor-binding motif ∼0.16 nm). The receptor-binding motif of RBD displayed a high degree of flexibility and the residues participated in the ligand interaction also portrayed higher RMSF indicating their participation in ligand recognition.\nThe intermolecular hydrogen bonds (H-bonds) between interacting atom pairs in a protein-ligand complex plays a vital role in the stability and molecular recognition process (Dehury et al., 2014). The intermolecular H-bonds were calculated with respect to time during the 100 ns MD simulation to see the dynamics stability RBD-ACE2-Naltrexone complex (Figure 4(A)). Though we observed an increased differential H-bonding during the initial 20 ns equilibration phase, however a stable trend with an average of ∼4.13 H-bonds are noticed from 60 to 100 ns. Close inspection of snapshots from MD revealed that some of the H-bonds were broken out during MD simulation, but at a later stage they well rewarded by new H-bonds, and hydrophobic contacts. This may be due to the structural re-orientation of ligand naltrexone in the binding pocket. The structural superposition of the docked complex with the cluster representative obtained from clustering analysis displayed Cα RMSD of 0.65 Å indicated that the complex retained its structural integrity throughout the simulation (Figure 4(B)). However, close observation of the ligand for the initial starting structure used MD revealed that the ligand tends to reorient within the binding site during MD (as shown in Figure 4(C)) but form a close tight network of hydrogen bonds and non-bonded contact with ACE and RBM of RBD. Analysis of the cluster representative revealed the crucial residues of RBD and ACE2 involved in the crucial interaction with naltrexone. Lys417 and Asp405 from RBD formed two hydrogen bonds with naltrexone, while Glu37 of ACE2-formed the lone hydrogen bond (Figure S2). Many electrostatic and hydrophobic contacts were also observed in the complex (Figure S2) where, Ile418, Gln409, and Tyr505 from RBD consistently formed close contact with ligand indicates their strong participation in the interaction mediated by naltrexone.\nFigure 4. Inter-molecular hydrogen bond dynamics and structural superposition of the initial complex with the simulated RBD-ACE2-naltrexone complex during 100 ns MD. (A) Dynamics stability of RBD-ACE2-naltrexone complex with respect to inter-molecular hydrogen bonds along the 100 ns time scale. (B) Structural superimposed view of the starting complex used for MD (green) and the snapshot obtained from clustering analysis (cyan) of MD trajectory during the last 50 ns. (C) Inter-molecular contacts of the docked complex and MD simulated 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