An update on inhibitors targeting RNA-dependent RNA polymerase for COVID-19 treatment: Promises and challenges

Xu, Xiao‐Ying; Chen, Yuheng; Lu, Xinyu; Zhang, Wanlin; Fang, Wenxiu; Yuan, L.; Wang, Xiaoyan

doi:10.1016/j.bcp.2022.115279

Cited by 16 publications

(18 citation statements)

References 150 publications

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“…Because the genome of SARS-CoV-2 is RNA-based, it consists of the following steps. (iv-a) Synthesis of RNA-dependent RNA polymerase (RdRp): SARS-CoV-2, which has (+)-strand RNA in its genome, first synthesizes RdRp encoded in the viral genome using host ribosomes [ 42 , 43 , 44 , 45 , 46 , 47 ]. Unlike DNA-dependent RNA polymerases in the host nucleus, RdRp is an enzymatic protein that synthesizes new RNA while reading the RNA sequence of the viral genome.…”

Section: Structural Characterization Of Sars-cov-2mentioning

confidence: 99%

Extracellular Vesicle-Based SARS-CoV-2 Vaccine

Matsuzaka

Yashiro

2023

Vaccines

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Messenger ribonucleic acid (RNA) vaccines are mainly used as SARS-CoV-2 vaccines. Despite several issues concerning storage, stability, effective period, and side effects, viral vector vaccines are widely used for the prevention and treatment of various diseases. Recently, viral vector-encapsulated extracellular vesicles (EVs) have been suggested as useful tools, owing to their safety and ability to escape from neutral antibodies. Herein, we summarize the possible cellular mechanisms underlying EV-based SARS-CoV-2 vaccines.

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Section: Structural Characterization Of Sars-cov-2mentioning

confidence: 99%

Extracellular Vesicle-Based SARS-CoV-2 Vaccine

Matsuzaka

Yashiro

2023

Vaccines

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“…In addition, the co-factors nsp7 and nsp8 enhance the enzymatic activity of nsp12 to catalyze viral RNA synthesis ( 55 ). Thus, the core polymerase complex nsp12-nsp7-nsp8 could be called the minimal core component of RNA synthesis ( 56 ). A schematic diagram of the core RdRp complex shows in Figure 2A .…”

Section: Inhibitors Of Sars-cov-2 Rna-dependent Rna Polymerasementioning

confidence: 99%

Oral GS-441524 derivatives: Next-generation inhibitors of SARS‐CoV‐2 RNA‐dependent RNA polymerase

Wang

Yang

Song³

2022

Front. Immunol.

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GS-441524, an RNA‐dependent RNA polymerase (RdRp) inhibitor, is a 1′-CN-substituted adenine C-nucleoside analog with broad-spectrum antiviral activity. However, the low oral bioavailability of GS‐441524 poses a challenge to its anti-SARS-CoV-2 efficacy. Remdesivir, the intravenously administered version (version 1.0) of GS-441524, is the first FDA-approved agent for SARS-CoV-2 treatment. However, clinical trials have presented conflicting evidence on the value of remdesivir in COVID-19. Therefore, oral GS-441524 derivatives (VV116, ATV006, and GS-621763; version 2.0, targeting highly conserved viral RdRp) could be considered as game-changers in treating COVID-19 because oral administration has the potential to maximize clinical benefits, including decreased duration of COVID-19 and reduced post-acute sequelae of SARS-CoV-2 infection, as well as limited side effects such as hepatic accumulation. This review summarizes the current research related to the oral derivatives of GS-441524, and provides important insights into the potential factors underlying the controversial observations regarding the clinical efficacy of remdesivir; overall, it offers an effective launching pad for developing an oral version of GS-441524.

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“…Viral RdRp is the main target for developing potent antiviral agents against SARS-CoV-2, not only due to its ability to accelerate the replication of RNA but also due to the lack of RdRp closely related host cell counterparts. Theoretically, the designed agent will selectively target the viral RdRp with no off-target side effects [ 23 ].…”

Section: Introductionmentioning

confidence: 99%