Cinnamic acid inhibits Zika virus by inhibiting RdRp activity

Chen, Yuting; Li, Laurent; Pan, Pan; Lao, Zizhao; Jiang-tao, XU; Li, Zonghui; Zhan, Shaofeng; Liu, Xiaohong; Wang, Wenbiao; Li, Geng

doi:10.1016/j.antiviral.2021.105117

Cited by 31 publications

(16 citation statements)

References 43 publications

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“…Since compound 4w has already been shown to be a HCV RdRp inhibitor, we speculated compound 4w may also act on ZIKV RdRp.We first detected whether 4w could interact with ZIKV RdRp by molecular docking method, and found that 4w can bind to ZIKV RdRp domain with low free energy ( Figures 4A,B ). ZIKV RdRp is mainly composed of three domains, namely palm domain (amino acid regions 321–488 and 542–608), finger domain (amino acid regions 489–541 and 609–714) and thumb (amino acid regions 715–903) ( Chen et al, 2021 ). In the docking results, it was found that 4w mainly binds to the palm domain of ZIKV RdRp, and preferentially binds to LYS468, PHE466, GLU465, and GLY467 amino acids in the palm region by hydrogen bonding force ( Figures 4C,D ).…”

Section: Resultsmentioning

confidence: 99%

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Identification of 6ω-cyclohexyl-2-(phenylamino carbonylmethylthio)pyrimidin-4(3H)-ones targeting the ZIKV NS5 RNA dependent RNA polymerase

Zhou

Xie²,

Xue³

et al. 2022

Front. Chem.

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Zika virus (ZIKV), a mosquito-borne flavivirus, is a global health concern because of its association with severe neurological disorders such as neonatal microcephaly and adult Guillain-Barre syndrome. Although many efforts have been made to combat ZIKV infection, there is currently no approved vaccines or antiviral drugs available and there is an urgent need to develop effective anti-ZIKV agents. In this study, 26 acetylarylamine-S-DACOs derivatives were prepared, and eight of them were found to have inhibitory activity against Zika virus. Among these substances, 2-[(4-cyclohexyl-5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)thio]-N-(3,5-difluorophenyl)acetamide (4w) with the best anti-ZIKV activity was selected for in-depth study of antiviral activity and mechanism of action. Here, we discovered 4w targeted on the ZIKV NS5 RNA -dependent RNA polymerase (RdRp), which exhibited good in vitro antiviral activity without cell species specificity, both at the protein level and at the RNA level can significantly inhibit ZIKV replication. Preliminary molecular docking studies showed that 4w preferentially binds to the palm region of NS5A RdRp through hydrogen bonding with residues such as LYS468, PHE466, GLU465, and GLY467. ZIKV NS5 RdRp enzyme activity experiment showed that 4w could directly inhibit ZIKV RdRp activity with EC50 = 11.38 ± 0.51 μM. In antiviral activity studies, 4w was found to inhibit ZIKV RNA replication with EC50 = 6.87 ± 1.21 μM. ZIKV-induced plaque formation was inhibited with EC50 = 7.65 ± 0.31 μM. In conclusion, our study disclosed that acetylarylamine-S-DACOs is a new active scaffolds against ZIKV, among which compound 4w was proved to be a potent novel anti-ZIKV compound target ZIKV RdRp protein. These promising results provide a future prospective for the development of ZIKV RdRp inhibitors.

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Section: Resultsmentioning

confidence: 99%

“…Then centrifuged at 20,000 × g at 4°C for 20 min. The supernatants were collected to prepare the samples, and the binding of 4w and ZIKV NS5 protein was analyzed by Western blotting ( Chen et al, 2020 ; Chen et al, 2021 ).…”

Section: Biology Assaymentioning

confidence: 99%

Identification of 6ω-cyclohexyl-2-(phenylamino carbonylmethylthio)pyrimidin-4(3H)-ones targeting the ZIKV NS5 RNA dependent RNA polymerase

Zhou

Xie²,

Xue³

et al. 2022

Front. Chem.

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“…Cinnamic acid has anti‐cancer, anti‐microbial, and anti‐diabetic properties. Its effects on Zika virus infection and neurological disorders have also been reported 27,28 . Larvicidal activity against mosquitoes has been demonstrated for DEHP 29 .…”

Section: Chemical Constituents Of Armentioning

confidence: 96%

“…Its effects on Zika virus infection and neurological disorders have also been reported. 27,28 Larvicidal activity against mosquitoes has been demonstrated for DEHP. 29 Dibutyl phthalate may induce oxidative stress in the zebrafish brain 30 and delayed neurodevelopment in mice.…”

Section: Aromatic Acids and Estersmentioning

confidence: 99%

A review of the phytochemical and pharmacological properties of Amauroderma rugosum

Zheng

Cheung²,

Leung

2022

The Kaohsiung J of Med Scie

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Amauroderma rugosum (AR) is a basidiomycete in the Ganodermataceae family that has been used traditionally to prevent epileptic attacks and constant crying in babies. However, AR has not been widely studied scientifically. In this review, we summarize the phytochemical components and pharmacological properties of AR that have been reported in the literature. Chemical analyses have revealed that the components of AR include sterols, flavonoids, fatty acids and esters, aromatic acids and esters, phenols, polysaccharides, and triterpenes. Pharmacological properties of AR include antioxidant, anti‐inflammatory, neuroprotective, anti‐cancer, anti‐hyperlipidemic, anti‐epileptic, and antibacterial effects. These findings suggest that AR and its bioactive ingredients have potential therapeutic applications, particularly for age‐related diseases.

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“…Hence, RdRp of NS5 plays a crucial role in viral genome replication and therefore, can serve as a potential anti-viral drug target (20). In fact, nucleoside and nonnucleoside inhibitors against NS5 RdRp from different viruses belonging to the flaviviridae family has been identified (21)(22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus

Malik

Vijayan

Jagannath

et al. 2022

Preprint

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Kyasanur forest disease is a neglected zoonotic disease caused by a single stranded RNA based flavivirus, the incidence of which, was first recorded in 1957, in the Southern part of India. Kyasanur forest disease virus is transmitted to monkeys and humans, through the infected tick bite of Haemophysalis spinigera. Kyasanur forest disease is a febrile illness, which in severe cases, results in neurological manifestations leading to mortality. The current treatment regimens are symptomatic and supportive in nature. There are no targeted therapies available for this disease. In this study, we evaluated the ability of the FDA approved drug, Sofosbuvir to inhibit the RNA dependent RNA polymerase activity of NS5 protein from Kyasanur forest disease virus. NS5 protein containing the N-terminal methyl transferase domain and C-terminal RNA dependent RNA polymerase domain was expressed in Escherichia coli and RNA dependent RNA polymerase activity, demonstrated with the purified protein. The RNA dependent RNA polymerase assay conditions were optimized, followed by determination of apparent Km,ATP. IC50 of Sofosbuvir against RNA dependent RNA polymerase activity was determined under the optimized conditions with the purified NS5 protein. Drug repurposing strategies can accelerate the development of targeted therapies for Kyasanur forest disease. This is the first demonstration of inhibition of RNA dependent RNA polymerase activity of Kyasanur forest disease virus with a small molecule inhibitor.

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Cinnamic acid inhibits Zika virus by inhibiting RdRp activity

Cited by 31 publications

References 43 publications

Identification of 6ω-cyclohexyl-2-(phenylamino carbonylmethylthio)pyrimidin-4(3H)-ones targeting the ZIKV NS5 RNA dependent RNA polymerase

Identification of 6ω-cyclohexyl-2-(phenylamino carbonylmethylthio)pyrimidin-4(3H)-ones targeting the ZIKV NS5 RNA dependent RNA polymerase

A review of the phytochemical and pharmacological properties of Amauroderma rugosum

Sofosbuvir and its tri-phosphate metabolite inhibit the RNA-dependent RNA polymerase activity of non-Structural protein 5 from the Kyasanur forest disease virus

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