The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)’s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19

Abstract

The unusual and interesting architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) was recently explored using Cryogenic Electron Microscopy (Cryo-EM), which revealed the presence of two distinctive binding cavities within the catalytic chamber. In this report, first, we mapped out and fully characterized the variations between the two binding sites, BS1 and BS2, for significant differences in their amino acid architecture, size, volume, and hydrophobicity. This was followed by investigating the preferential binding of eight antiviral agents to each of the two binding sites, BS1 and BS2, to understand the fundamental factors that govern the preferential binding of each drug to each binding site. Results showed that, in general, hydrophobic drugs, such as remdesivir and sofosbuvir, bind better to both binding sites than relatively less hydrophobic drugs, such as alovudine, molnupiravir, zidovudine, favilavir, and ribavirin. However, suramin, which is a highly hydrophobic drug, unexpectedly showed overall weaker binding affinities in both binding sites when compared to other drugs. This unexpected observation may be attributed to its high binding solvation energy, which disfavors overall binding of suramin in both binding sites. On the other hand, hydrophobic drugs displayed higher binding affinities towards BS1 due to its higher hydrophobic architecture when compared to BS2, while less hydrophobic drugs did not show a significant difference in binding affinities in both binding sites. Analysis of binding energy contributions revealed that the most favorable components are the ΔEele, ΔEvdw, and ΔGgas, whereas ΔGsol was unfavorable. The ΔEele and ΔGgas for hydrophobic drugs were enough to balance the unfavorable ΔGsol, leaving the ΔEvdw to be the most determining factor of the total binding energy. The information presented in this report will provide guidelines for tailoring SARS-CoV-2 inhibitors with enhanced binding profiles.

Synergism between remdesivir and ribavirin leads to SARS‐CoV‐2 extinction in cell culture

“…Competition of RDV and RBV for binding to the polymerase-RNA complex (a model is presented in Figure S9 in the Supplementary information) seems unlikely as a synergy-promoting mechanism and more so because of the indication that the binding of RDV to the polymerase is stronger than the binding of RBV, as suggested by the docking work (Metwally et al, 2023). Additional structural and F I G U R E 6 Numbers of different point mutations and haplotypes in mutant spectra of SARS-CoV-2 populations grown in the absence or presence of remdesivir, ribavirin or their combinations.…”

Molecular Understanding of ACE-2 and HLA-Conferred Differential Susceptibility to COVID-19: Host-Directed Insights Opening New Windows in COVID-19 Therapeutics

“…Owing to the high virulence, pathogenicity, and contagiousness of SARS-CoV-2, in the second week of March 2020, the WHO declared COVID-19 as a pandemic [ 8 ]. The COVID-19 outbreak caused by SARS-CoV-2 received a great deal of interest across the world [ 9 ]. As of February 21st, 2023, more than 757, 264, 511 cases had occurred from the COVID-19 disease [ 10 ].…”