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10.1128/AAC.02237-20

http://scihub22266oqcxt.onion/10.1128/AAC.02237-20
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33229429!7849018!33229429
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suck abstract from ncbi


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pmid33229429      Antimicrob+Agents+Chemother 2021 ; 65 (2): ä
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  • Off-Target In Vitro Profiling Demonstrates that Remdesivir Is a Highly Selective Antiviral Agent #MMPMID33229429
  • Xu Y; Barauskas O; Kim C; Babusis D; Murakami E; Kornyeyev D; Lee G; Stepan G; Perron M; Bannister R; Schultz BE; Sakowicz R; Porter D; Cihlar T; Feng JY
  • Antimicrob Agents Chemother 2021[Jan]; 65 (2): ä PMID33229429show ga
  • Remdesivir (RDV, GS-5734), the first FDA-approved antiviral for the treatment of COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. It is intracellularly metabolized into the active triphosphate form, which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases. RDV has broad-spectrum activity against members of the coronavirus family, such as SARS-CoV-2, SARS-CoV, and MERS-CoV, as well as filoviruses and paramyxoviruses. To assess the potential for off-target toxicity, RDV was evaluated in a set of cellular and biochemical assays. Cytotoxicity was evaluated in a set of relevant human cell lines and primary cells. In addition, RDV was evaluated for mitochondrial toxicity under aerobic and anaerobic metabolic conditions, and for the effects on mitochondrial DNA content, mitochondrial protein synthesis, cellular respiration, and induction of reactive oxygen species. Last, the active 5'-triphosphate metabolite of RDV, GS-443902, was evaluated for potential interaction with human DNA and RNA polymerases. Among all of the human cells tested under 5 to 14 days of continuous exposure, the 50% cytotoxic concentration (CC(50)) values of RDV ranged from 1.7 to >20 muM, resulting in selectivity indices (SI, CC(50)/EC(50)) from >170 to 20,000, with respect to RDV anti-SARS-CoV-2 activity (50% effective concentration [EC(50)] of 9.9 nM in human airway epithelial cells). Overall, the cellular and biochemical assays demonstrated a low potential for RDV to elicit off-target toxicity, including mitochondria-specific toxicity, consistent with the reported clinical safety profile.
  • |*COVID-19 Drug Treatment[MESH]
  • |Adenosine Monophosphate/*analogs & derivatives/chemistry/pharmacology[MESH]
  • |Alanine/*analogs & derivatives/chemistry/pharmacology[MESH]
  • |Antiviral Agents/chemistry/*pharmacology[MESH]
  • |COVID-19/virology[MESH]
  • |Cell Line[MESH]
  • |Epithelial Cells/drug effects[MESH]
  • |Humans[MESH]
  • |Inhibitory Concentration 50[MESH]
  • |Mitochondria/drug effects[MESH]
  • |Primary Cell Culture[MESH]


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