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

ABSTRACT: The highly transmissible variants of SARS-CoV-2, the causative pathogen of the COVID-19 pandemic, bring new waves of infection worldwide. Identification of effective therapeutic drugs to combat the COVID-19 pandemic is an urgent global need. RNA-dependent RNA polymerase (RdRp), an essential enzyme for viral RNA replication, is the most promising target for antiviral drug research since it has no counterpart in human cells and shows the highest conservation across coronaviruses. This review summarizes recent progress in studies of RdRp inhibitors, focusing on interactions between these inhibitors and the enzyme complex, based on structural analysis, and their effectiveness. In addition, we propose new possible strategies to address the shortcomings of current inhibitors, which may guide the development of novel efficient inhibitors to combat COVID-19.

SUBMITTER: Xu X

PROVIDER: S-EPMC9535928 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Xu Xiaoying X Chen Yuheng Y Lu Xinyu X Zhang Wanlin W Fang Wenxiu W Yuan Luping L Wang Xiaoyan X

Biochemical pharmacology 20221006

The highly transmissible variants of SARS-CoV-2, the causative pathogen of the COVID-19 pandemic, bring new waves of infection worldwide. Identification of effective therapeutic drugs to combat the COVID-19 pandemic is an urgent global need. RNA-dependent RNA polymerase (RdRp), an essential enzyme for viral RNA replication, is the most promising target for antiviral drug research since it has no counterpart in human cells and shows the highest conservation across coronaviruses. This review summa ...[more]

PMID: 36209840

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Project description:COVID-19, caused by Severe Acute Respiratory Syndrome Corona Virus 2, is declared a Global Pandemic by WHO in early 2020. In the present situation, though more than 180 vaccine candidates with some already approved for emergency use, are currently in development against SARS-CoV-2, their safety and efficacy data is still in a very preliminary stage to recognize them as a new treatment, which demands an utmost emergency for the development of an alternative anti-COVID-19 drug sine qua non for a COVID-19 free world. Since RNA-dependent RNA polymerase (RdRp) is an essential protein involved in replicating the virus, it can be held as a potential drug target. We were keen to explore the plant-based product against RdRp and analyze its inhibitory potential to treat COVID-19. A unique collection of 248 plant compounds were selected based on their antiviral activity published in previous literature and were subjected to molecular docking analysis against the catalytic sub-unit of RdRp. The docking study was followed by a pharmacokinetics analysis and molecular dynamics simulation study of the selected best-docked compounds. Tellimagrandin I, SaikosaponinB2, Hesperidin and (-)-Epigallocatechin Gallate were the most prominent ones that showed strong binding affinity toward RdRp. All the compounds mentioned showed satisfactory pharmacokinetics properties and remained stabilized at their respective binding sites during the Molecular dynamics simulation. Additionally, we calculated the free-binding energy/the binding properties of RdRp-ligand complexes with the connection of MM/GBSA. Interestingly, we observe that SaikosaponinB2 gives the best binding affinity (∆Gbinding = -42.43 kcal/mol) in the MM/GBSA assay. Whereas, least activity is observed for Hesperidin (∆Gbinding = -22.72 kcal/mol). Overall our study unveiled the feasibility of the SaikosaponinB2 to serve as potential molecules for developing an effective therapy against COVID-19 by inhibiting one of its most crucial replication proteins, RdRp.

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

Publications

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

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