dc.contributor.author | Onwubiko, Nichodemus O. | |
dc.contributor.author | Diaz, Suraya | |
dc.contributor.author | Krecmerova, Marcela | |
dc.contributor.author | Nasheuer, Heinz-Peter | |
dc.date.accessioned | 2021-01-04T16:03:08Z | |
dc.date.issued | 2020-12-07 | |
dc.identifier.citation | Onwubiko, Nichodemus O., Diaz, Suraya, Krecmerova, Marcela, & Nasheuer, Heinz-Peter. (2020). Alkoxyalkyl esters of nucleotide analogs inhibit polyomavirus DNA replication and large T antigen activities. Antimicrobial Agents and Chemotherapy. doi:10.1128/AAC.01641-20 | en_IE |
dc.identifier.issn | 1098-6596 | |
dc.identifier.uri | http://hdl.handle.net/10379/16401 | |
dc.description.abstract | Polyomavirus-related infections are ubiqutious in immunocompromised individuals and in some cases are intractable and fatal. Due to lack of approved drugs to treat polyomavirus infections, cidofovir, a phosphonate nucleotide analog approved to treat cytomegalovirus infections has been repurposed as anti-polyomavirus agent. Cidofovir has been modified in various ways to improve its efficacies as broad-spectrum antiviral agent. However, the actual mechanisms and targets of cidofovir and its modified derivatives as anti-polyomavirus agents are still under research. Here, polyomavirus large tumor antigens (Tag) activities were identified as the viral target of cidofovir derivatives. The alkoxyalkyl-ester derivatives of cidofovir efficiently inhibit polyomavirus DNA replication in cell-free human extracts and a viral in vitro replication system only utilizing purified proteins. We present evidence that DNA helicase, and DNA binding activities of polyomavirus Tags are diminished in the presence of low concentrations of alkoxyalkyl-ester derivatives of cidofovir suggesting that the inhibition of viral DNA replication is at least in part mediated by inhibiting ssDNA and dsDNA binding activities of Tags. These findings show that the alkoxyalkyl-ester derivatives of cidofovir are effective in vitro without undergoing further conversions and conclude that the inhibitory mechanisms of nucleotide analog-based drugs are more complex than previously believed. | en_IE |
dc.description.sponsorship | This work was supported by funding from the Else Kröner-Fresenius-Stiftung (EKFS
2013_A215) and the PML Consortium (Washington, USA; RIB1099) to HPN, and grant
No. LM2018133 by the Czech National Node to the European Infrastructure for
Translational Medicine EATRIS-CZ. NOO was supported by a NUI Galway College of
Science fellowship. The authors thank Chimerix Inc for providing some of the
nucleotide analogs studied, Ms Patricia Nyland for expert technical assistance, Dr. Zoë
Popper, NUI Galway, for providing a TLC chamber and Ms. Lydia Anusiem for help
with proofreading. | en_IE |
dc.format | application/pdf | en_IE |
dc.language.iso | en | en_IE |
dc.publisher | American Society for Microbiology Journals | en_IE |
dc.relation.ispartof | Antimicrobial Agents And Chemotherapy | en |
dc.rights | Attribution-NonCommercial-NoDerivs 3.0 Ireland | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/3.0/ie/ | |
dc.subject | Acute Kidney Injury | en_IE |
dc.subject | Stem Cell | en_IE |
dc.subject | Inflammation | en_IE |
dc.subject | Sepsis | en_IE |
dc.subject | Cell Therapy | en_IE |
dc.subject | Macrophages | en_IE |
dc.subject | Lymphocytes | en_IE |
dc.subject | Exosome | en_IE |
dc.subject | Cytokines | en_IE |
dc.subject | Chemokine | en_IE |
dc.title | Alkoxyalkyl esters of nucleotide analogs inhibit polyomavirus DNA replication and large T antigen activities | en_IE |
dc.type | Article | en_IE |
dc.date.updated | 2021-01-04T14:19:13Z | |
dc.identifier.doi | 10.1128/AAC.01641-20 | |
dc.local.publishedsource | https://doi.org/10.1128/AAC.01641-20 | en_IE |
dc.description.peer-reviewed | peer-reviewed | |
dc.description.embargo | 2021-06-07 | |
dc.internal.rssid | 24218451 | |
dc.local.contact | Heinz-Peter Nasheuer, 2fn, Rm Bms 2010, Biochemistry S, Bioresearch Building, Nui Galway, Galway. 2430 Email: heinz.nasheuer@nuigalway.ie | |
dc.local.copyrightchecked | Yes | |
dc.local.version | ACCEPTED | |
nui.item.downloads | 74 | |