Piece of the Puzzle: Remdesivir disassemble the multimeric SARS-CoV-2 RNA-dependent RNA Polymerase Non-Structural Proteins (RdRp-NSPs) complex

Abstract

The recently emerged SARS-like coronavirus (SARS-CoV-2) has continued to spread rapidly among humans with alarming upsurges in global mortality rates. A major key to tackling this virus is to disrupt its RNA replication process as previously reported for Remdesivir (Rem-P3). For the first time, we modeled the binding of Rem-P3 to SARS-CoV-2 RdRp-NSPs complex, a multimeric assembly that drives viral RNA replication in human hosts. Findings revealed that while ATP-binding stabilized the replicative tripartite, Rem-P3 disintegrated the RdRp-NSP complex, starting with the detachment of the NSP7-NSP8 heterodimer followed by minimal displacement of the second NSP8 subunit (NSP8II). More so, Rem-P3 interacted with a relatively higher affinity (ΔGbind) while inducing high perturbations across the RdRp-NSP domains. D452, T556, V557, S682, and D760 were identified for their crucial roles in stacking the cyano-adenosine and 3,4-dihydroxyoxolan rings of Rem-P3 while its flexible P3 tail extended towards the palm domain blocking D618 and K798; a residue-pair identified for essential roles in RNA replication. However, ATP folded away from D618 indicative of a more coordinated binding favorable for nucleotide polymerization. We believe findings from this study will significantly contribute to the structure-based design of novel disruptors of the SARS-CoV-2 RNA replicative machinery.

Perversely Expressed Long Noncoding Rnas Can Alter Host Response and Viral Proliferation in SARS-CoV-2 Infection

“…RNA exosome complex is involved in 3 processing of various stable RNA species and is crucial for RNA quality control in the nucleus [114], thus Nsp8 binding may be fundamental to diminishing the capacity of exosome to act against viral mRNAs. Antiviral drug remdesivir has been predicted to target and disassemble this complex [115,116]. Interaction of EXOSC5 protein with KCNQ1OT1 and SNHG8 can modulate this interaction.…”

Allosteric activation of SARS-CoV-2 RdRp by remdesivir triphosphate and other phosphorylated nucleotides

“…Among these drugs, remdesivir received the most attention even though the estimates of its clinical effectiveness range from moderate to insignificant ( Al-Abdouh et al, 2021 ; Kaka et al, 2021 ). RdRp readily uses RTP as a substrate in place of ATP and temporarily stalls downstream from the site of RMP incorporation ( Gordon et al, 2020 ; Kokic et al, 2021 ); however, the proposed mechanisms of its action vary widely, from RdRp stalling to RNA chain termination to disassembly of the RdRp ( Bravo et al, 2021 ; Olotu et al, 2021 ; Tchesnokov et al, 2020 ). It is presently unclear whether antiviral effects of remdesivir are due to delays in RNA synthesis or to errors in RNA messages, as is the case with another purine analog, favipiravir ( Shannon et al, 2020b ).…”