Antiviral therapeutics directed against RNA dependent RNA polymerases from positive-sense viruses

Bhatia, Sonam; Narayanan, Naveen; Nagpal, Shilpi; Nair, D.T.

doi:10.1016/j.mam.2021.101005

Cited by 6 publications

(7 citation statements)

References 169 publications

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“…[52] In contrast, NNIs exert antiviral activity by altering interactions between the enzyme substrate and the active core catalytic site of RdRp, which is expected to have fewer off-target effects and better target specificity. [53] To date, several RdRp NNIs have been developed for COVID-19, including baicalein, corilagin and lycorine, most of these NNIs are plant-derived natural products. Baicalein from Scutellaria baicalensis can block viral replication in cell culture systems by inhibiting the RdRp activity of SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

Gossypol Broadly Inhibits Coronaviruses by Targeting RNA‐Dependent RNA Polymerases

Wang

Wen

et al. 2022

Advanced Science

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Outbreaks of coronaviruses (CoVs), especially severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have posed serious threats to humans and animals, which urgently calls for effective broad‐spectrum antivirals. RNA‐dependent RNA polymerase (RdRp) plays an essential role in viral RNA synthesis and is an ideal pan‐coronaviral therapeutic target. Herein, based on cryo‐electron microscopy and biochemical approaches, gossypol (GOS) is identified from 881 natural products to directly block SARS‐CoV‐2 RdRp, thus inhibiting SARS‐CoV‐2 replication in both cellular and mouse infection models. GOS also acts as a potent inhibitor against the SARS‐CoV‐2 variant of concern (VOC) and exerts same inhibitory effects toward mutated RdRps of VOCs as the RdRp of the original SARS‐CoV‐2. Moreover, that the RdRp inhibitor GOS has broad‐spectrum anti‐coronavirus activity against alphacoronaviruses (porcine epidemic diarrhea virus and swine acute diarrhea syndrome coronavirus), betacoronaviruses (SARS‐CoV‐2), gammacoronaviruses (avian infectious bronchitis virus), and deltacoronaviruses (porcine deltacoronavirus) is showed. The findings demonstrate that GOS may serve as a promising lead compound for combating the ongoing COVID‐19 pandemic and other coronavirus outbreaks.

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Section: Discussionmentioning

confidence: 99%

Gossypol Broadly Inhibits Coronaviruses by Targeting RNA‐Dependent RNA Polymerases

Wang

Wen

et al. 2022

Advanced Science

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“…Catalysis results in the generation of a pyrophosphate, a dinucleotide and translocation. The remaining dinucleotide can be elongated via NTP hydrolysis [ 46 , 47 ].…”

Section: Structure and Function Of Ns3 And Ns5mentioning

confidence: 99%

“…This hand can adopt an open and closed conformation, mediated by movements of motifs F and G [ 52 ]. The open conformation exposes the active site during initiation and elongation, while the closed conformation clasps around the incoming nucleotide to facilitate addition [ 46 ]. The active site consists of three conserved aspartates located in motifs A and D which are critical for catalysis.…”

Section: Structure and Function Of Ns3 And Ns5mentioning

confidence: 99%

The Role of the Flavivirus Replicase in Viral Diversity and Adaptation

Caldwell

Pata

Ciota

2022

Viruses

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Flaviviruses include several emerging and re-emerging arboviruses which cause millions of infections each year. Although relatively well-studied, much remains unknown regarding the mechanisms and means by which these viruses readily alternate and adapt to different hosts and environments. Here, we review a subset of the different aspects of flaviviral biology which impact host switching and viral fitness. These include the mechanism of replication and structural biology of the NS3 and NS5 proteins, which reproduce the viral genome; rates of mutation resulting from this replication and the role of mutational frequency in viral fitness; and the theory of quasispecies evolution and how it contributes to our understanding of genetic and phenotypic plasticity.

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“…One of the major strategies used in the RdRp enzyme inhibition process is the use of nucleotide triphosphate analogs which prevent the binding of natural substrates through steric exclusion [19].…”

Section: Rna-dependent Rna Polymerase (Rdrp) Inhibitorsmentioning

confidence: 99%

“…Later then, SARS-CoV-2 was declared as a global pandemic by WHO on March 11, 2020, due to the rapid increase in its pathogenicity and rate of transmission. According to the WHO (COVID- 19) Dashboard, as of 24 September 2021, a total of 230,418,451 confirmed cases of COVID-19 have been reported worldwide, including 4,724,876 deaths (https://covid19.who.int). This massive loss of population worldwide due to the SARS-CoV-2 pandemic has raised the urgent call for antiviral drugs for treatment/prevention against COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Rna-Dependent Rna Polymerase (Rdrp) Inhibitor Drugs Against Sars-Cov-2: A Molecular Docking Study

GADO

ALAGÖZ

2022

Ankara Universitesi Eczacilik Fakultesi Dergisi

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Objective: SARS-CoV-2 associated viral pandemic was first reported in Wuhan, China, in December 2019. Due to the rapid increase in its pathogenicity, SARS-CoV-2 was declared a global pandemic by WHO on March 11, 2020. For that reason, determining the most attractive viral protein targets became a must. One of the most important target proteins is SARS-COV-2 RNA-dependent RNA polymerase (RdRp) on which COVID-19 depends in its replication process. This study aimed to examine the possible interactions between RdRp and the most promising RdRp nucleoside inhibitors especially Purine nucleoside analogs, to detect the most important residues that commonly interact with RdRp's inhibitors and to investigate whether if there any mutations have been observed so far in these residues or not.Material and Method: Molecular docking studies were carried out using AutoDock Vina between SARS-CoV-2 RdRp and drugs approved against different viral RdRps (Galidesivir, Remdesivir, Ribavirin, Sofosbuvir, and Favipiravir) as well as physiological nucleotides (ATP and GTP). Based on the obtained results, a detailed surface-interaction analysis was also performed using Pymol and Discovery Studio Visualizer software for the models that exhibited the most suitable location and configuration in space.Result and Discussion: All the tested molecules were able to bind to SARS-CoV-2 RdRp successfully. Also, they all commonly interact with 9 different amino acids (Arg553, Arg555, Asp618, Asp623, Ser682, Asn691, Ser759, Asp760, and Asp761), and 3 different Template-primer RNA nucleotides (U10, A11, and U20) causing inhibition of viral RdRp via non obligate RNA chain termination.

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Antiviral therapeutics directed against RNA dependent RNA polymerases from positive-sense viruses

Cited by 6 publications

References 169 publications

Gossypol Broadly Inhibits Coronaviruses by Targeting RNA‐Dependent RNA Polymerases

Gossypol Broadly Inhibits Coronaviruses by Targeting RNA‐Dependent RNA Polymerases

The Role of the Flavivirus Replicase in Viral Diversity and Adaptation

Rna-Dependent Rna Polymerase (Rdrp) Inhibitor Drugs Against Sars-Cov-2: A Molecular Docking Study

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