Antiretroviral drug activity and potential for pre-exposure prophylaxis against COVID-19 and HIV infection

Abstract

COVID-19 is the disease caused by SARS-CoV-2 which has led to 2,643,000 deaths worldwide, a number which is rapidly increasing. Urgent studies to identify new antiviral drugs, repurpose existing drugs, or identify drugs that can target the overactive immune response are ongoing. Antiretroviral drugs (ARVs) have been tested in past human coronavirus infections, and also against SARS-CoV-2, but a trial of lopinavir and ritonavir failed to show any clinical benefit in COVID-19. However, there is limited data as to the course of COVID-19 in people living with HIV, with some studies showing a decreased mortality for those taking certain ARV regimens. We hypothesized that ARVs other than lopinavir and ritonavir might be responsible for some protection against the progression of COVID-19. Here, we used chemoinformatic analyses to predict which ARVs would bind and potentially inhibit the SARS-CoV-2 main protease (Mpro) or RNA-dependent-RNA-polymerase (RdRp) enzymes in silico. The drugs predicted to bind the SARS-CoV-2 Mpro included the protease inhibitors atazanavir and indinavir. The ARVs predicted to bind the catalytic site of the RdRp included Nucleoside Reverse Transcriptase Inhibitors, abacavir, emtricitabine, zidovudine, and tenofovir. Existing or new combinations of antiretroviral drugs could potentially prevent or ameliorate the course of COVID-19 if shown to inhibit SARS-CoV-2 in vitro and in clinical trials. Further studies are needed to establish the activity of ARVs for treatment or prevention of SARS-CoV-2 infection .Communicated by Ramaswamy H. Sarma.

Keywords: COVID-19; HIV; PrEP; SARS-CoV-2; antiretrovirals; docking.

Figure 1.

Overall schematic for the methods used in this paper and our significant results. Molecules are docked to key residues of the viral enzymes. The HIV ARVs that are predicted to bind to designated catalytic sites of the viral enzymes are those listed next to either bracket. The red dots indicate the designated catalytic sites for the purpose of this study. The binding and potential inhibition of these enzymes would disrupt the replication machinery of this virus, as shown by the replication schematic.

Figure 2.

Ligand interaction diagrams in 2D from induced fit docking of (a) atazanavir, and (b) indinavir to the Mpro.

Figure 3.

Ligand interaction diagrams in 2D from induced fit docking of (a) abacavir, (b) emtricitabine, (c) tenofovir, and (d) zidovudine.

Figure 4.

Protein-ligand RMSD plots for the Mpro, (a) atazanavir, and (c) indinavir complexes. For Cα atoms of the Mpro the RMSD is represented by the blue line (scale on left). The RMSD of the ligands are represented by the red line with the scale to the right of the figures in the top row. Please note that all graphs have various scales. The x-axis scale is in nanoseconds, the y-axis is in Angstroms. Protein RMSF plots in bottom row, of (b) atazanavir, and (d) indinavir complexed with Mpro. Secondary structural elements of alpha helices and beta strands are represented by highlighted red and blue backgrounds respectively. Protein ligand contacts are marked with green vertical bars. Please note the varying scales used in each graph.

Figure 5.

Protein ligand contacts of the Mpro with the (a) atazanavir, and (b) indinavir ligands respectively. Hydrogen bonds represented in green, purple representing hydrophobic interactions, pink for ionic, and blue for water bridges.

Figure 6.

Detailed protein ligand interactions which occur over time in the MD simulation are shown for (a) atazanavir, and (b) indinavir. Only interactions which occur for more than 30% of the simulation are shown in each.

Figure 7.

RMSD plots in left column, for the Cα (blue, scale left) from MD analysis of RdRp (a) abacavir, (b) emtricitabine, (c) tenofovir, and (d) zidovudine complexes. The ligand RMSD plot (magenta, scale right). Protein RMSF plots in right column, of (e) abacavir, (f) emtricitabine, (g) tenofovir, and (h) zidovudine complexed with RdRp. Secondary structural elements of alpha helices and beta strands are represented by highlighted red and blue backgrounds respectively. Protein ligand contacts are marked with green vertical bars. Please note the varying scales in each graph.

Figure 8.

Protein ligand contacts of the RdRp with the (a) abacavir, (b) emtricitabine, (c) tenofovir, and (d) zidovudine ligands respectively. Hydrogen bonds represented in green, purple representing hydrophobic interactions, pink for ionic, and blue for water bridges.

Figure 9.

Detailed protein ligand interactions which occur over time in the MD simulation are shown for the RdRp- (a) abacavir, (b) emtricitabine, (c) tenofovir, and (d) zidovudine complexes. Only interactions which occur for at least 30% of the simulation are shown in each. For more detailed interactions across each please see the supplemental material. The Glide XP docking scores utilize an empirical scoring function which approximates the ligand binding free energy, when the ligands bind to the designated catalytic sites of either the Mpro or RdRp. More negative numbers suggest more free energy associated with the predicted binding event (Table 1, Table 2).