Hsp90 inhibitor AT-533 blocks HSV-1 nuclear egress and assembly

Li, Feng; Jin, Fujun; Wang, Yiliang; Zheng, Danlin; Liu, Junwei; Zhang, Zhen; Wang, Rongze; Dong, Dong; Zheng, Kai

doi:10.1093/jb/mvy066

Cited by 19 publications

(20 citation statements)

References 37 publications

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“…Subsequently, the TCID50/mL was converted into plaque-forming units (PFU)/mL [31]. The assays were conducted as described in our previous studies [32,33]. Briefly, 1 × 10 4 or 1.5 × 10 5 Vero cells were seeded in 96-well or 24-well plates to perform CCK8 assay or plaque assay, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…After 72 h, the OD value of the cells in 96-well plates was detected by CCK8 assay. The cells in 24-well plates were fixed by paraformaldehyde for 0.5 h, and strained with crystal violet for 0.5 h. Finally, the number of plaques was counted to calculate the inhibition rate of virus infection as described previously [32]. The 50% effective concentration (EC 50 ) was also calculated as described previously [33].…”

Section: Methodsmentioning

confidence: 99%

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Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection

Song

et al. 2019

Viruses

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Infection of Herpes simplex virus 1 (HSV-1) induces severe clinical disorders, such as herpes simplex encephalitis and keratitis. Acyclovir (ACV) is the current therapeutic drug against viral infection and ACV-resistant strains have gradually emerged, leading to the requirement for novel antiviral agents. In this study, we exhibited the antiviral activity of amentoflavone, a naturally occurring biflavonoid, toward HSV-1 and ACV-resistant strains. Amentoflavone significantly inhibited infection of HSV-1 (F strain), as well as several ACV-resistant strains including HSV-1/106, HSV-1/153 and HSV-1/Blue at high concentrations. Time-of-drug-addition assay further revealed that amentoflavone mainly impaired HSV-1 early infection. More detailed study demonstrated that amentoflavone affected cofilin-mediated F-actin reorganization and reduced the intracellular transportation of HSV-1 from the cell membrane to the nucleus. In addition, amentoflavone substantially decreased transcription of viral immediate early genes. Collectively, amentoflavone showed strong antiviral activity against HSV-1 and ACV-resistant strains, and amentoflavone could be a promising therapeutic candidate for HSV-1 pathogenesis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection

Song

et al. 2019

Viruses

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“…An HSV with a mutation in the N-terminal domain of U L 31 displays hampered translocation of capsids from the nucleus to the cytoplasm, which was linked with deficiencies in primary envelopment (Roller et al, 2010 ; Funk et al, 2015 ). Interestingly, the Hsp90 protein inhibitor AT-533 has been shown to block viral nuclear egress by inhibiting the functions U L 31 and U L 34 in cells infected with HSV-1 (Li et al, 2018 ). On the other hand, NEC also recruits viral kinases U S 3 and U L 13, as well as cellular protein kinases, such as PKC that phosphorylate and locally disrupt the nuclear lamina which facilitates capsid access to the INM by an envelopment process (Bjerke and Roller, 2006 ; Cano-Monreal et al, 2009 ; Wild et al, 2015 ).…”

Section: Viral Capsid Assembly In the Nucleus And Transport To The Cymentioning

confidence: 99%

Experimental Dissection of the Lytic Replication Cycles of Herpes Simplex Viruses in vitro

et al. 2018

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Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) produce lifelong infections and are highly prevalent in the human population. Both viruses elicit numerous clinical manifestations and produce mild-to-severe diseases that affect the skin, eyes, and brain, among others. Despite the existence of numerous antivirals against HSV, such as acyclovir and acyclovir-related analogs, virus variants that are resistant to these compounds can be isolated from immunosuppressed individuals. For such isolates, second-line drugs can be used, yet they frequently produce adverse side effects. Furthermore, topical antivirals for treating cutaneous HSV infections usually display poor to moderate efficacy. Hence, better or novel anti-HSV antivirals are needed and details on their mechanisms of action would be insightful for improving their efficacy and identifying specific molecular targets. Here, we review and dissect the lytic replication cycles of herpes simplex viruses, discussing key steps involved in cell infection and the processes that yield new virions. Additionally, we review and discuss rapid, easy-to-perform and simple experimental approaches for studying key steps involved in HSV replication to facilitate the identification of the mechanisms of action of anti-HSV compounds.

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“…SNX-25a (70) also significantly suppressed the HSV-1 virus titers, and inhibited nucleocapsid egress from the nucleus. 159 Many other HSP90 inhibitors have also shown definitive antiviral activities against a panel of virus strains. 160,161 Although around 17 HSP90 inhibitors are under development in clinical trials, they are all for cancer indication and none is being tested for antiviral purpose albeit with well-established preclinical results.…”

Section: Heat Shock Protein 90mentioning

confidence: 99%

Medicinal chemistry strategies toward host targeting antiviral agents

2020

Medicinal Research Reviews

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Direct-acting antiviral agents (DAAs) represent a class of drugs targeting viral proteins and have been demonstrated to be very successful in combating viral infections in clinic. However, DAAs suffer from several inherent limitations, including narrow-spectrum antiviral profiles and liability to drug resistance, and hence there are still unmet needs in the treatment of viral infections. In comparison, host targeting antivirals (HTAs) target host factors for antiviral treatment. Since host proteins are probably broadly required for various viral infections, HTAs are not only perceived, but also demonstrated to exhibit broad-spectrum antiviral activities. In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. In this review, we summarize various host proteins as antiviral targets from a medicinal chemistry prospective. Challenges and issues associated with HTAs are also discussed. K E Y W O R D S broad-spectrum antivirals, direct-acting antiviral agents, drug resistance, host targeting antiviral agents

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Hsp90 inhibitor AT-533 blocks HSV-1 nuclear egress and assembly

Cited by 19 publications

References 37 publications

Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection

Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection

Experimental Dissection of the Lytic Replication Cycles of Herpes Simplex Viruses in vitro

Medicinal chemistry strategies toward host targeting antiviral agents

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