Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors

Lin, Yuan; Zhang, Hongjuan; Song, Weibao; Si, Shuyi; Han, Yan‐Xing; Jiang, Jian‐Dong

doi:10.1016/j.ijantimicag.2019.07.010

Cited by 32 publications

(36 citation statements)

References 18 publications

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“…The T agg values of NS5 ranged from 44.6 to 47.8°C, which shows that lycorine binds to NS5 and protects its stability. NS5 is the largest nonstructural protein, and contains an N-terminal methyltransferase (MTase) domain and a Cterminal RdRp domain (Lin et al, 2019). The RdRp domain, which interacts with other viral and host factors to form a replicase complex responsible for their replication, is required for RNA synthesis and is essential for flavivirus replication.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we designed in vitro RNA polymerase assays to verify whether lycorine inhibits RdRp activity, and the experiment results showed that lycorine treatment inhibited RdRp activity. RdRp would be an ideal target option for anti-ZIKV infection because human host cells are devoid of RdRp (Lin et al, 2019). Therefore, further studies are required to define the mechanism by which lycorine acts on RdRp.…”

Section: Discussionmentioning

confidence: 99%

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Antiviral activity of lycorine against Zika virus in vivo and in vitro

et al. 2020

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The emergence and re-emergence of Zika virus (ZIKV), is a cause for international concern. These highly pathogenic arboviruses represent a serious health burden in tropical and subtropical areas worldwide. Despite these burdens, antiviral therapies do not exist, and inhibitors of ZIKV are therefore urgently needed. To elucidate the anti-ZIKV effect of lycorine, we used reverse transcription-quantitative real-time PCR (qRT-PCR), immunofluorescence, Westernwestern blot, and plaque forming assay to analyse viral RNA (vRNA), viral protein, progeny virus counts, and validated inhibitors in vitro using a variety of cell lines. Additionally, we found that lycorine acts post-infection according to time-of-addition assay, and inhibits RdRp activity. Lycorine protected AG6 mice against ZIKV-induced lethality by decreasing the viral load in the blood. Due to its potency and ability to target ZIKV infection in vivo and in vitro, lycorine might offer promising therapeutic possibilities for combatting ZIKV infections in the future.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antiviral activity of lycorine against Zika virus in vivo and in vitro

et al. 2020

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“…Furthermore, residue D535 was mutated to A535 while residue D692 (outside the active site) was mutated to A692. This led to the weak binding of UA to the RdRp since A535 s IC 50 was 20-fold higher while A692 s IC 50 remained unchanged compared to the wild type RdRp thus proving that residue D535 is critical for UA binding [56].…”

Section: Structural Studiesmentioning

confidence: 99%

Importance of Zika Virus NS5 Protein for Viral Replication

2019

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Zika virus is the latest addition to an ever-growing list of arboviruses that are causing outbreaks with serious consequences. A few mild cases were recorded between 1960 and 1980 until the first major outbreak in 2007 on Yap Island. This was followed by more severe outbreaks in French Polynesia (2013) and Brazil (2015), which significantly increased both Guillain-Barre syndrome and microcephaly cases. No current vaccines or treatments are available, however, recent studies have taken interest in the NS5 protein which encodes both the viral methyltransferase and RNA-dependent RNA polymerase. This makes it important for viral replication alongside other important functions such as inhibiting the innate immune system thus ensuring virus survival and replication. Structural studies can help design inhibitors, while biochemical studies can help understand the various mechanisms utilized by NS5 thus counteracting them might inhibit or abolish the viral infection. Drug repurposing targeting the NS5 protein has also proven to be an effective tool since hundreds of thousands of compounds can be screened therefore saving time and resources, moreover information on these compounds might already be available especially if they are used to treat other ailments.

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“…However, emetine has demonstrated potential toxicity toward the fetus, indicating that its use should be avoided during pregnancy [35]. In addition, 10-undecenoic acid zinc salt (UA) was another non-nucleoside drug that inhibits ZIKV replication by targeting RdRp [48]. UA is commonly used in clinics to treat fungal infections [49].…”

Section: Inhibitors Of Rdrpmentioning

confidence: 99%

Repurposing clinical drugs is a promising strategy to discover drugs against Zika virus infection

Song

Zhang

et al. 2020

Front. Med.

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Zika virus (ZIKV) is an emerging pathogen associated with neurological complications, such as Guillain-Barré syndrome in adults and microcephaly in fetuses and newborns. This mosquito-borne flavivirus causes important social and sanitary problems owing to its rapid dissemination. However, the development of antivirals against ZIKV is lagging. Although various strategies have been used to study anti-ZIKV agents, approved drugs or vaccines for the treatment (or prevention) of ZIKV infections are currently unavailable. Repurposing clinically approved drugs could be an effective approach to quickly respond to an emergency outbreak of ZIKV infections. The well-established safety profiles and optimal dosage of these clinically approved drugs could provide an economical, safe, and efficacious approach to address ZIKV infections. This review focuses on the recent research and development of agents against ZIKV infection by repurposing clinical drugs. Their characteristics, targets, and potential use in anti-ZIKV therapy are presented. This review provides an update and some successful strategies in the search for anti-ZIKV agents are given.

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Identification and characterization of Zika virus NS5 RNA-dependent RNA polymerase inhibitors

Cited by 32 publications

References 18 publications

Antiviral activity of lycorine against Zika virus in vivo and in vitro

Antiviral activity of lycorine against Zika virus in vivo and in vitro

Importance of Zika Virus NS5 Protein for Viral Replication

Repurposing clinical drugs is a promising strategy to discover drugs against Zika virus infection

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