Glibenclamide inhibits BK polyomavirus infection in kidney cells through CFTR blockade

Panou, Margarita-Maria; Antoni, Michelle; Morgan, Ethan L.; Loundras, Eleni-Anna; Wasson, Christopher W.; Welberry-Smith, Matthew; Mankouri, Jamel; Macdonald, Andrew

doi:10.1016/j.antiviral.2020.104778

Cited by 17 publications

(9 citation statements)

References 66 publications

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“…BK polyomavirus (BKPyV) is a potentially fatal pathogen in patients undergoing solid organ transplantation. Panou et al demonstrated that the pharmacological and genetic disruption of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl − channel could reduce BKPyV infection in primary kidney cell models ( Figure 1 I) [ 42 ]. Time of addition assays using the CFTR inhibitors CFTR 172 and glibenclamide, combined with the assessment of exposure of VP2/VP3 minor capsid proteins, indicated a role for CFTR in the trafficking of BKPyV to the ER.…”

Section: Ion Channels Involved In Viral Entrymentioning

confidence: 99%

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Charlton

Pearson

Hover

et al. 2020

Viruses

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Ion channels play key roles in almost all facets of cellular physiology and have emerged as key host cell factors for a multitude of viral infections. A catalogue of ion channel-blocking drugs have been shown to possess antiviral activity, some of which are in widespread human usage for ion channel-related diseases, highlighting new potential for drug repurposing. The emergence of ion channel–virus interactions has also revealed the intriguing possibility that channelopathies may explain some commonly observed virus induced pathologies. This field is rapidly evolving and an up-to-date summary of new discoveries can inform future perspectives. We herein discuss the role of ion channels during viral lifecycles, describe the recently identified ion channel drugs that can inhibit viral infections, and highlight the potential contribution of ion channels to virus-mediated disease.

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Section: Ion Channels Involved In Viral Entrymentioning

confidence: 99%

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Charlton

Pearson

Hover

et al. 2020

Viruses

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“…Similar to mPyV, BKPyV has also been attributed to require low pH prior to localization within the ER [ 97 , 157 ]. Recently, the anti-diabetic drug, glibenclamide, which blocks the cystic fibrosis transmembrane conductance regulator (CFTR), impeded BKPyV infection [ 158 ]. Importantly, the maximum inhibitory effect of this drug was found to be 4 hpi, suggesting that the hindrance in infection occurs during trafficking of the virus to the ER [ 158 ].…”

Section: Traffickingmentioning

confidence: 99%

“…Recently, the anti-diabetic drug, glibenclamide, which blocks the cystic fibrosis transmembrane conductance regulator (CFTR), impeded BKPyV infection [ 158 ]. Importantly, the maximum inhibitory effect of this drug was found to be 4 hpi, suggesting that the hindrance in infection occurs during trafficking of the virus to the ER [ 158 ]. Collectively this highlights the importance of ion channel regulation during endosomal trafficking of BKPyV.…”

Section: Traffickingmentioning

confidence: 99%

Taking the Scenic Route: Polyomaviruses Utilize Multiple Pathways to Reach the Same Destination

Mayberry

Maginnis

2020

Viruses

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Members of the Polyomaviridae family differ in their host range, pathogenesis, and disease severity. To date, some of the most studied polyomaviruses include human JC, BK, and Merkel cell polyomavirus and non-human subspecies murine and simian virus 40 (SV40) polyomavirus. Although dichotomies in host range and pathogenesis exist, overlapping features of the infectious cycle illuminate the similarities within this virus family. Of particular interest to human health, JC, BK, and Merkel cell polyomavirus have all been linked to critical, often fatal, illnesses, emphasizing the importance of understanding the underlying viral infections that result in the onset of these diseases. As there are significant overlaps in the capacity of polyomaviruses to cause disease in their respective hosts, recent advancements in characterizing the infectious life cycle of non-human murine and SV40 polyomaviruses are key to understanding diseases caused by their human counterparts. This review focuses on the molecular mechanisms by which different polyomaviruses hijack cellular processes to attach to host cells, internalize, traffic within the cytoplasm, and disassemble within the endoplasmic reticulum (ER), prior to delivery to the nucleus for viral replication. Unraveling the fundamental processes that facilitate polyomavirus infection provides deeper insight into the conserved mechanisms of the infectious process shared within this virus family, while also highlighting critical unique viral features.

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“…Ion channels are emerging as key factors required during virus replicative cycles, examples including the roles for potassium (K + ) channels in Bunyamwera virus (BUNV) infection 9 10 ; two-pore calcium (Ca 2+ ) channels in Ebola virus (EBOV) infection 11 and chloride (Cl − ) channels in chikungunya virus (CHIKV), hepatitis C virus (HCV), BK polyomavirus and Merkel cell polyomavirus infection. [12][13][14][15] Cl − channels are diverse families of proteins that regulate cell excitability and fluid and osmolyte secretion in lung epithelial cells. Over 40 genes are linked to Cl − conductances which can be categorised into voltage-gated Cl − channels (ClC), ligand-gated Clchannels, cystic fibrosis transmembrane conductance regulator (CFTR), volume-regulated anion channels and Ca 2+ -activated Cl − channel (CaCC) families.…”

Section: Respiratory Infectionmentioning

confidence: 99%

TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection

Pearson

Todd

Ahrends

et al. 2020

Thorax

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IntroductionHuman respiratory syncytial virus (HRSV) is a common cause of respiratory tract infections (RTIs) globally and is one of the most fatal infectious diseases for infants in developing countries. Of those infected, 25%–40% aged ≤1 year develop severe lower RTIs leading to pneumonia and bronchiolitis, with ~10% requiring hospitalisation. Evidence also suggests that HRSV infection early in life is a major cause of adult asthma. There is no HRSV vaccine, and the only clinically approved treatment is immunoprophylaxis that is expensive and only moderately effective. New anti-HRSV therapeutic strategies are therefore urgently required.MethodsIt is now established that viruses require cellular ion channel functionality to infect cells. Here, we infected human lung epithelial cell lines and ex vivo human lung slices with HRSV in the presence of a defined panel of chloride (Cl−) channel modulators to investigate their role during the HRSV life-cycle.ResultsWe demonstrate the requirement for TMEM16A, a calcium-activated Cl− channel, for HRSV infection. Time-of-addition assays revealed that the TMEM16A blockers inhibit HRSV at a postentry stage of the virus life-cycle, showing activity as a postexposure prophylaxis. Another important negative-sense RNA respiratory pathogen influenza virus was also inhibited by the TMEM16A-specific inhibitor T16Ainh-A01.DiscussionThese findings reveal TMEM16A as an exciting target for future host-directed antiviral therapeutics.

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Glibenclamide inhibits BK polyomavirus infection in kidney cells through CFTR blockade

Cited by 17 publications

References 66 publications

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Ion Channels as Therapeutic Targets for Viral Infections: Further Discoveries and Future Perspectives

Taking the Scenic Route: Polyomaviruses Utilize Multiple Pathways to Reach the Same Destination

TMEM16A/ANO1 calcium-activated chloride channel as a novel target for the treatment of human respiratory syncytial virus infection

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