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Inhibition of polyomavirus DNA replication by nucleotide analogs
Onwubiko, Nichodemus Okechukwu
Polyomaviruses are non-evenloped circular DNA viruses that cause severe polyomavirus-associated diseases in immune compromised individuals. The diseases associated with these viruses have been on the rise due to myriad of immune compromising conditions to which individuals are exposed. Hitherto, no cure has been approved for the treatment of these viral diseases. Nucleotide analogs (mainly cidofovir, CDV, and its derivatives) have been used without approval for the treatment of the diseases but the actual mechanism and targets of these analogs used to treat polyomavirus-associated diseases are not yet known. Here, I describe the identification of the cellular and viral targets of the analogs and the mechanism, by which these analogs inhibit polyomavirus DNA replication. The fatty-ester linked analogs (HDP-CDV and HDEacCDV) show strong inhibition of polyomavirus DNA replication in concentration-dependent manner. Further analyses reveal that these analogs target the human DNA polymerases α-primase and DNA polymerases δ and inhibit DNA synthesis of the two enzymes. The inhibition of DNA synthesis by DNA polymerase α-primase with respect to dCTP is mixed competitive and noncompetitive whereas with respect to dTTP, dATP, and dGTP, the inhibition mechanism is noncompetitive. These fatty-ester analogs also inhibit the ATPase and helicase activities of the viral large tumor antigens of polyomaviruses studied in a concentration-dependent manner but do not inhibit DNA relaxation activity of human topoisomerase I. Neither the fatty-ester moiety alone, the parent nucleotide analog, CDV, nor its non-fatty ester derivatives inhibited the activities of the viral and cellular enzymes investigated. In addition, to delineating the targets of the fatty-ester linked analogs and their mechanism of inhibition of polyomavirus DNA replication these results also suggest that the fatty-ester linked analogs acquired novel allosteric inhibition and are active without undergoing further modifications, which may account for the increased inhibition efficiencies previously reported for the fatty-ester modified nucleotide analogs. This data further suggests that fatty-ester modification could be a novel active metabolite in the in vivo metabolism of nucleotide analog-based therapies 2019-01-30
Keyword(s): Biochemistry; Molecular biology; DNA; Polyomavirus; Nucleotide; Analogs
Publication Date:
2017
Type: Doctoral thesis
Peer-Reviewed: Unknown
Institution: NUI Galway
Supervisor(s): Nasheuer, Heinz-Peter
College of Science NUIG
First Indexed: 2018-01-31 06:32:20 Last Updated: 2018-03-07 06:22:30