Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly

Kang, Jung Ah; Kim, Songwon; Park, Minji; Park, Hyun Jin; Kim, Jeong Hyun; Park, Sanghyeok; Hwang, Jeong Ryul; Kim, Yong Chul; Kim, Yoon Jun; Cho, Yuri; Jin, Mi Sun; Park, Sung‐Gyoo

doi:10.1038/s41467-019-10200-5

Cited by 54 publications

(47 citation statements)

References 60 publications

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“…e grid map of various atoms of the ligands and receptor was generated by AutoGrid. It was previously reported that His51, Asp75, and Ser135 play an important role in the functioning activity of NS2B-NS3 protease [20,21]; thus, in the docking procedure, the grid box was chosen such that it incorporates these key residues. e energy scoring grid was prepared in x × y × z directions (80 × 80 × 80) with a grid spacing of 0.375Å.…”

Section: Ligands and Receptormentioning

confidence: 99%

Designs, Synthesis, Docking Studies, and Biological Evaluation of Novel Berberine Derivatives Targeting Zika Virus

Nguyen

et al. 2021

Journal of Chemistry

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The World Health Organization has designated Zika virus (ZIKV) as a dangerous, mosquito-borne flaviviral pathogen that was recently found to be responsible for a dramatically increased number of microcephaly cases and other congenital abnormalities in fetuses and newborns. There is neither a vaccine to prevent nor a drug to treat ZIKA virus infections, at the present time. Berberine (BBR) is a promising drug approved by FDA against flaviviral dengue virus, and BBR derivatives are of great interest in antiviral drug development. In this study, we synthesized eight BBR derivatives by introducing benzyl groups at the C-13 position of BBR and converting to respective 8-oxoberberine derivatives, performed molecular docking analysis, and evaluated their anti-Zika virus activity utilizing a cell‐based phenotypic assay. Binding mode analysis, absolute binding free energy calculation, and structure-activity relationship studies of these compounds with ZIKV NS3 receptor were collected. Amongst these studied compounds, compound 4d with a structure of 13-(2,6-difluoro)-benzylberberine showed high binding affinity (docking score of −7.31 kcal/mol) towards ZIKV NS2B-NS3 protease with critical binding formed within the active site. In the cell-based assay, compound 4d displayed the highest antiviral efficacy against ZIKV with a selective index (SI) of 15.3, with 3.7-fold greater than that of berberine. Together, our study suggests that the potential ZIKV NS2B-NS3 protease inhibitor, compound 4d, is the best alternative to BBR and, further, extends an assuring platform for developing antiviral competitive inhibitors against ZIKV infection.

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Section: Ligands and Receptormentioning

confidence: 99%

Designs, Synthesis, Docking Studies, and Biological Evaluation of Novel Berberine Derivatives Targeting Zika Virus

Nguyen

et al. 2021

Journal of Chemistry

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“…6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone (ciclopirox or CPX) and specifically it's olamine salt 6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone 2-aminoethanol salt (ciclopirox olamine or CPX-O) are antifungal, topical agents used in a variety of formulations such as gels, creams, shampoos for treatment of cutaneous fungal infections (19). However, over the last decade, the wide use of CPX or CPX-O in other diseases has been recognized (20)(21)(22). Furthermore, the safe therapeutic response of CPX-O has been tested in various animals including pigs and dogs (20).…”

Section: Introductionmentioning

confidence: 99%

Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease

Radadiya¹,

Thornton²,

Puri³

et al. 2021

JCI Insight

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Despite the recent launch of Tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox (CPX) or its olamine salt (CPX-O) are contained in number of commercially available antifungal agents. CPX is also reported to possess anticancer activity. Several mechanisms of action have been proposed including chelation of iron and inhibition of iron dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human PKD cyst-lining epithelial cells cultured in a 3D collagen matrix. To assess in vivo role of CPX-O, we treated PKD mice with CPX-O. CPX-O reduced the kidney-to-body weight ratios of PKD mice. This was also associated with decreased cell proliferation, decreased cystic area and improved renal function. Ferritin levels were significantly elevated in cystic kidneys of PKD mice, and CPX-O treatment reduced renal ferritin levels. The reduction in ferritin was associated with increased ferritinophagy marker, NCOA4 which reversed upon CPX-O treatment in PKD mice. Interestingly, these effects on ferritin appeared independent of iron. These data suggest that CPX-O can induce ferritin degradation via ferritinophagy which is associated with decreased cyst growth progression in PKD mice. Most importantly these data indicate that CPX-O has the potential to treat autosomal dominant PKD.

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“…Ciclopirox synergizes with entecavir (a deoxyguanosine analog) and tenofovir (a nucleotide analog reverse transcriptase inhibitor) and could become an important addition to orally active drug cocktails that actually eradicate the infection. For the peer review companion article, see Kang et al 23…”

Section: A Common Antifungal Might Eradicate Hepatitis B Virus Infectionmentioning

confidence: 99%

Drug Repurposing Patent Applications January–March 2020

Mucke¹

2020

ASSAY and Drug Development Technologies

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Ciclopirox inhibits Hepatitis B Virus secretion by blocking capsid assembly

Cited by 54 publications

References 60 publications

Designs, Synthesis, Docking Studies, and Biological Evaluation of Novel Berberine Derivatives Targeting Zika Virus

Designs, Synthesis, Docking Studies, and Biological Evaluation of Novel Berberine Derivatives Targeting Zika Virus

Ciclopirox olamine induces ferritinophagy and reduces cyst burden in polycystic kidney disease

Drug Repurposing Patent Applications January–March 2020

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