Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors

Bonafoux, D.; Nanthakumar, Suganthini; Bandarage, Upul K.; Memmott, Christine; Lowe, Derek; Aronov, Alex M.; Bhisetti, Govinda; Bonanno, Kenneth; Coll, Joyce T.; Leeman, Joshua R.; Lepre, Christopher A.; Fan, Li; Perola, Emanuele; Rijnbrand, René; Taylor, W. P.; Wilson, Dean; Zhou, Yi; Zwahlen, Jacque; Haar, Ernst ter

doi:10.1021/acs.jmedchem.6b00486

Cited by 23 publications

(23 citation statements)

References 15 publications

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“…Efforts to target the helicase activity of BK/JC-TAg have been unsuccessful. 94 , 95 The VP1 capsid protein is an attractive target due to its critical role in multiple phases of the BKV lifecycle, such as assembly, entry, trafficking, and disassembly, 3 , 5 and its implication in BKV-associated nephropathy pathogenesis. 96 Capsid modifiers have recently been pharmacologically validated and are in clinical development for other viruses.…”

Section: Managementmentioning

confidence: 99%

Advances in BK Virus Complications in Organ Transplantation and Beyond

et al. 2020

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Reactivation of BK virus (BKV) remains a dreaded complication in immunosuppressed states. Conventionally, BKV is known as a cause for BKV-associated nephropathy and allograft dysfunction in kidney transplant recipients. However, emerging studies have shown its negative impact on native kidney function and patient survival in other transplants and its potential role in diseases such as cancer. Because BKV-associated nephropathy is driven by immunosuppression, reduction in the latter is a convenient standard of care. However, this strategy is risk prone due to the development of donor-specific antibodies affecting long-term allograft survival. Despite its pathogenic role, there is a distinct lack of effective anti-BKV therapeutics. This limitation combined with increased morbidity and health care cost of BKV-associated diseases add to the complexity of BKV management. While summarizing recent advances in the pathogenesis of BKV-associated nephropathy and its reactivation in other organ transplants, this review illustrates the limitations of current and emerging therapeutic options and provides a compelling argument for an effective targeted anti-BKV drug.

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Section: Managementmentioning

confidence: 99%

Advances in BK Virus Complications in Organ Transplantation and Beyond

et al. 2020

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“…We compared the crystal structure of EV71 2C 116–329 with all structures in the PDB using the Dali server (http://ekhidna.biocenter.helsinki.fi/dali_server/). The best hit was large T antigen (LTAg) of the human polyomavirus John Cunningham virus (JCV), a hexameric DNA helicase sharing a 75% sequence identity with SV40 LTAg ( 24 ). The root mean square deviation value between EV71 2C 116–329 and JCV LTAg (PDB code: 5J4Y) is 2.7 Å for 117 superimposed Cα atoms.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of 2C helicase from enterovirus 71

et al. 2017

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“…4A), the cells may be suitable for high-throughput screening and may be able to substitute for the cervical carcinoma cell line C33A that was previously used to study JCV DNA replication (42). Finding an inhibitor that is selective for T-ag-dependent JCV DNA replication will be a significant step toward developing a treatment for PML and related diseases (40,(93)(94)(95).…”

Section: Discussionmentioning

confidence: 99%

“…Molecular modeling. An image of the JCV T-ag helicase domain based on a threaded model of the SV40 helicase domain (Protein Data Bank [PDB] code 4GDF) was generated using the program PyMOL (102) (note that the recently solved structure of the JCV helicase domain [40] was not used because it did not include electron density for residue H514).…”

Section: Methodsmentioning

confidence: 99%

“…The major gene product encoded by the early region of the JCV genome is large T antigen (T-ag), a 688-residue modular protein that has an N-terminal J domain, an origin binding domain, and C-terminal helicase domain (reviewed in references [33][34][35][36][37]; the structures of the JCV T-ag origin binding domain (38,39) and helicase domains (40) have been recently solved. JCV T-ag accumulates in the nuclei of glial cells derived from PML patients (41).…”

Section: The G144 Oligodendrocyte Precursor Cell Line Supports Robustmentioning

confidence: 99%

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Replication of JC Virus DNA in the G144 Oligodendrocyte Cell Line Is Dependent Upon Akt

Peterson

Lin

Shin

et al. 2017

J Virol

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Progressive multifocal leukoencephalopathy (PML) is an often-fatal demyelinating disease of the central nervous system. PML results when oligodendrocytes within immunocompromised individuals are infected with the human JC virus (JCV). We have identified an oligodendrocyte precursor cell line, termed G144, that supports robust levels of JCV DNA replication, a central part of the JCV life cycle. In addition, we have determined that JC virus readily infects G144 cells. Furthermore, we have determined that JCV DNA replication in G144 cells is stimulated by myristoylated (i.e., constitutively active) Akt and reduced by the Akt-specific inhibitor MK2206. Thus, this oligodendrocyte-based model system will be useful for a number of purposes, such as studies of JCV infection, establishing key pathways needed for the regulation of JCV DNA replication, and identifying inhibitors of this process. The disease progressive multifocal leukoencephalopathy (PML) is caused by the infection of particular brain cells, termed oligodendrocytes, by the JC virus. Studies of PML, however, have been hampered by the lack of an immortalized human cell line derived from oligodendrocytes. Here, we report that the G144 oligodendrocyte cell line supports both infection by JC virus and robust levels of JCV DNA replication. Moreover, we have established that the Akt pathway regulates JCV DNA replication and that JCV DNA replication can be inhibited by MK2206, a compound that is specific for Akt. These and related findings suggest that we have established a powerful oligodendrocyte-based model system for studies of JCV-dependent PML.

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Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors

Cited by 23 publications

References 15 publications

Advances in BK Virus Complications in Organ Transplantation and Beyond

Advances in BK Virus Complications in Organ Transplantation and Beyond

Crystal structure of 2C helicase from enterovirus 71

Replication of JC Virus DNA in the G144 Oligodendrocyte Cell Line Is Dependent Upon Akt

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