Abstract:Highlights d Kinetics show stalling after 3-4 remdesivirs are incorporated d The stalled complex partially escapes in the presence of high NTP concentrations d Stalling is due to a block in translocation after incorporation of the fourth RMP d The translocation block is a steric clash between the cyano group of RMP and the protein
“…While the S861A mutant shows a subtle reduction in delayed chain-termination [ 26 , 27 •• ], RNA synthesis is not inhibited with the S861 G mutant [ 27 •• ]. These results guided structural studies that confirmed the original model [ 28 , 29 ]. Figure 1 How does RDV work against SARS-CoV-2?…”
The nucleotide analogue prodrug remdesivir remains the only FDA-approved antiviral small molecule for the treatment of infection with SARS-CoV-2. Biochemical studies revealed that the active form of the drug targets the viral RNA-dependent RNA polymerase and causes delayed chain-termination. Delayed chain-termination is incomplete, but the continuation of RNA synthesis enables a partial escape from viral proofreading. Remdesivir becomes embedded in the copy of the RNA genome that later serves as a template. Incorporation of an incoming nucleotide triphosphate is now inhibited by the modified template. Knowledge on the mechanism of action matters. Enzymatic inhibition links to antiviral effects in cell cultures, animal models and viral load reduction in patients, which provides the logical chain that is expected for a direct acting antiviral. Hence, remdesivir also serves as a benchmark in current drug development efforts that will hopefully lead to orally available treatments to the benefit of a broader population.
“…While the S861A mutant shows a subtle reduction in delayed chain-termination [ 26 , 27 •• ], RNA synthesis is not inhibited with the S861 G mutant [ 27 •• ]. These results guided structural studies that confirmed the original model [ 28 , 29 ]. Figure 1 How does RDV work against SARS-CoV-2?…”
The nucleotide analogue prodrug remdesivir remains the only FDA-approved antiviral small molecule for the treatment of infection with SARS-CoV-2. Biochemical studies revealed that the active form of the drug targets the viral RNA-dependent RNA polymerase and causes delayed chain-termination. Delayed chain-termination is incomplete, but the continuation of RNA synthesis enables a partial escape from viral proofreading. Remdesivir becomes embedded in the copy of the RNA genome that later serves as a template. Incorporation of an incoming nucleotide triphosphate is now inhibited by the modified template. Knowledge on the mechanism of action matters. Enzymatic inhibition links to antiviral effects in cell cultures, animal models and viral load reduction in patients, which provides the logical chain that is expected for a direct acting antiviral. Hence, remdesivir also serves as a benchmark in current drug development efforts that will hopefully lead to orally available treatments to the benefit of a broader population.
“…Nevertheless, remdesivir is virostatic by blocking the RNA translocation. Cryo-EM reconstruction of a remdesivir-stalled RNA-dependent RNA polymerase complex revealed that three or four remdesivir monophosphates are incorporated in the active site [ 52 ]. Therefore, remdesivir serves as a suitable positive control due to its strong virus inhibition in cell culture models [ 53 ].…”
Blood-pressure-lowering drugs are proposed to foster SARS-CoV-2 infection by pharmacological upregulation of angiotensin-converting enzyme 2 (ACE2), the binding partner of the virus spike (S) protein, located on the surface of the host cells. Conversely, it is postulated that angiotensin–renin system antagonists may prevent lung damage caused by SARS-CoV-2 infection, by reducing angiotensin II levels, which can induce permeability of lung endothelial barrier via its interaction with the AT1 receptor (AT1R). Methods: We have investigated the influence of the ACE inhibitors (lisinopril, captopril) and the AT1 antagonists (telmisartan, olmesartan) on the level of ACE2 mRNA and protein expression as well as their influence on the cytopathic effect of SARS-CoV-2 and on the cell barrier integrity in a Caco-2 cell model. Results: The drugs revealed no effect on ACE2 mRNA and protein expression. ACE inhibitors and AT1R antagonist olmesartan did not influence the infection rate of SARS-CoV-2 and were unable to prevent the SARS-CoV-2-induced cell barrier disturbance. A concentration of 25 µg/mL telmisartan significantly reduced the virus replication rate. Conclusion: ACE inhibitors and AT1R antagonist showed neither beneficial nor detrimental effects on SARS-CoV-2-infection and cell barrier integrity in vitro at pharmacologically relevant concentrations.
“…A key advantage for Rdv over other nucleotide analogues is its enhanced selectivity over ATP by SARS/MERS-CoVs RdRps [124] , [125] . Following incorporation of Rdv-TP, the RdRp elongates until stalling when the Rdv 1′-ribose cyano group clashes with the sidechain of nsp12 S861, hindering further translocation [124] , [125] , [126] , [127] , [128] ( Fig. 9 ).…”
Section: Antivirals Targeting the Rdrpmentioning
confidence: 99%
“…This observation led to initial descriptions of the mechanism of inhibition as delayed chain termination. However, under the saturating nucleotide concentrations occurring in the cellular milieu, the translocation block is surmounted [99] , [126] , [127] , [128] , suggesting that Rdv is incorporated throughout the nascently synthesized CoV genome [124] , [127] . Fig.…”
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