Cellular IMPDH enzyme activity is a potential target for the inhibition of Chikungunya virus replication and virus induced apoptosis in cultured mammalian cells

Khan, Mohsin; Dhanwani, Rekha; Patro, Nisha; Rao, P. Venkata; Parida, Manmohan

doi:10.1016/j.antiviral.2010.10.009

Cited by 88 publications

(104 citation statements)

References 29 publications

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“…Compounds which resulted in Ն70% inhibition of CHIKV infection were classified as hits. Our primary screen identified 44 compounds as positive hits, including mycophenolic acid, which has recently been reported to be effective in inhibiting the replication of CHIKV (19). Having mycophenolic acid independently identified as a hit in our primary screen further indicated the reliability of our primary screening assay in identifying putative anti-CHIKV inhibitors.…”

Section: Discussionmentioning

confidence: 79%

“…Among the drugs that have been licensed by the U.S. FDA, ribavirin is an example of a drug which is known to act by targeting a host component. Ribavirin is used for the treatment of hepatitis C virus and pediatric respiratory syncytial virus infections (19). Ribavirin is known to deplete intracellular GTP pools by inhibiting a host enzyme, IMP dehydrogenase.…”

Section: Figmentioning

confidence: 99%

“…Previous studies have reported anti-CHIKV activities for some compounds in vitro. These include chloroquine (14,15), furin inhibitors (16), arbidol (17,18), mycophenolic acid (19), and a combination of ribavirin and alpha interferon (20). Of these, only chloroquine has been tested in vivo.…”

mentioning

confidence: 99%

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Inhibition of Chikungunya Virus Replication by Harringtonine, a Novel Antiviral That Suppresses Viral Protein Expression

Kaur

Thiruchelvan²,

Lee³

et al. 2013

Antimicrob Agents Chemother

149

123

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Chikungunya virus (CHIKV) is a mosquito-transmitted virus that has reemerged as a significant public health threat in the last decade. Since the 2005-2006 chikungunya fever epidemic in the Indian Ocean island of La Réunion, millions of people in more than 40 countries have been infected. Despite this, there is currently no antiviral treatment for chikungunya infection. In this study, an immunofluorescence-based screening platform was developed to identify potential inhibitors of CHIKV infection. A primary screen was performed using a highly purified natural product compound library, and 44 compounds exhibiting >70% inhibition of CHIKV infection were identified as positive hits. Among these, four were selected for dose-dependent inhibition assays to confirm their anti-CHIKV activity. Harringtonine, a cephalotaxine alkaloid, displayed potent inhibition of CHIKV infection (50% effective concentration [EC 50 ] ‫؍‬ 0.24 M) with minimal cytotoxicity and was selected for elucidation of its antiviral mechanism. Time-of-addition studies, cotreatment assays, and direct transfection of viral genomic RNA indicated that harringtonine inhibited an early stage of the CHIKV replication cycle which occurred after viral entry into cells. In addition, quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses indicated that harringtonine affects CHIKV RNA production as well as viral protein expression. Treatment of harringtonine against Sindbis virus, a related alphavirus, suggested that harringtonine could inhibit other alphaviruses. This study suggests for the first time that harringtonine exerts its antiviral effects by inhibiting CHIKV viral protein synthesis.

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Section: Discussionmentioning

confidence: 79%

Section: Figmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Chikungunya Virus Replication by Harringtonine, a Novel Antiviral That Suppresses Viral Protein Expression

Kaur

Thiruchelvan²,

Lee³

et al. 2013

Antimicrob Agents Chemother

149

123

View full text Add to dashboard Cite

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“…6 Several chemical compounds have been reported to exhibit weak anti-CHIKV activity. They include apigenin, 6 6-azauridine, 6 chloroquine, 7 chrysin, 6 (5,7-dihydroxy)flavones, 6 interferon, mycophenolic acid, 8 prothipendyl, 6 ribavirin, 9 silibin, 6 etc. In 2011, arbidol and its two derived metabolites were tested in vitro on the CHIKV by use of two cell lines in pre-and post-infection conditions.…”

Section: Introductionmentioning

confidence: 99%

Benzouracil–coumarin–arene conjugates as inhibiting agents for chikungunya virus

et al. 2015

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ABSTRACT. Chikungunya virus (CHIKV) causes an arboviral disease and was first recognized in epidemic form in East Africa in [1952][1953]. The virus is primarily transmitted through mosquitoes and the resulting disease, chikungunya fever, is found in nearly 40 countries.Neither an effective vaccine nor a specific antiviral drug exists for treatments of Chikungunya fever. Thus 25 new triply conjugated compounds of uracil−coumarin−arene were designed and synthesized as potential inhibiting agents. Their chemical structures were determined unambiguously by spectroscopic methods, including single-crystal X-ray diffraction crystallography. The three nuclei in these conjugates were connected by specially designed −SCH2− and −OSO2− joints. Five of these new conjugates were found to inhibit CHIKV Vero 2 cells with significant potency (EC50 = 10.2-19.1 µM) and showed low toxicity (CC50 = 75-178 µM). The selective index values were 9.3-11.5 for three conjugates. By analysis of the data from the anti-viral assays, the structure-activity relationship is derived on the basis of the nature of the uracil nucleus, the joint between the nuclei, and the functional group attached to the arene nucleus.

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“…23 More recently, it was shown that mycophenolic acid, a potent inhibitor of guanine nucleotide biosynthesis, efficiently blocked CHIKV replication in vitro. 24 Few other molecules, including 5,7-dihydroxyflavones, were recently characterized as CHIKV inhibitors by using phenotypic assays based on CHIKV replicons or recombinant viruses expressing reporter genes. Whether these different molecules represent leads for the development, an in vivo therapy remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

A Phenotypic Assay to Identify Chikungunya Virus Inhibitors Targeting the Nonstructural Protein nsP2

et al. 2013

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These authors contributed equally to this work. AbstractChikungunya virus (CHIKV) is a mosquito-transmitted pathogen responsible for an acute infection of abrupt onset, characterized by high fever, polyarthralgia, myalgia, headaches, chills, and rash. In 2006, CHIKV was responsible for an epidemic outbreak of unprecedented magnitude in the Indian Ocean, stressing the need for therapeutic approaches. Since then, we have acquired a better understanding of CHIKV biology, but we are still missing active molecules against this reemerging pathogen. We recently reported that the nonstructural nsP2 protein of CHIKV induces a transcriptional shutoff that allows the virus to block cellular antiviral response. This was demonstrated using various luciferase-based reporter gene assays, including a trans-reporter system where Gal4 DNA binding domain is fused to Fos transcription factor. Here, we turned this assay into a high-throughput screening system to identify small molecules targeting nsP2-mediated shutoff. Among 3040 molecules tested, we identified one natural compound that partially blocks nsP2 activity and inhibits CHIKV replication in vitro. This proof of concept suggests that similar functional assays could be developed to target other viral proteins mediating a cellular shutoff and identify innovative therapeutic molecules.

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Cellular IMPDH enzyme activity is a potential target for the inhibition of Chikungunya virus replication and virus induced apoptosis in cultured mammalian cells

Cited by 88 publications

References 29 publications

Inhibition of Chikungunya Virus Replication by Harringtonine, a Novel Antiviral That Suppresses Viral Protein Expression

Inhibition of Chikungunya Virus Replication by Harringtonine, a Novel Antiviral That Suppresses Viral Protein Expression

Benzouracil–coumarin–arene conjugates as inhibiting agents for chikungunya virus

A Phenotypic Assay to Identify Chikungunya Virus Inhibitors Targeting the Nonstructural Protein nsP2

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