Structural Basis for Inhibition of Human Primase by
Arabinofuranosyl Nucleoside Analogues Fludarabine and Vidarabine
Posted on 2019-09-11 - 13:42
Nucleoside analogues are widely used
in clinical practice as chemotherapy
drugs. Arabinose nucleoside derivatives such as fludarabine are effective
in the treatment of patients with acute and chronic leukemias and
non-Hodgkin’s lymphomas. Although nucleoside analogues are
generally known to function by inhibiting DNA synthesis in rapidly
proliferating cells, the identity of their in vivo targets and mechanism of action are often not known in molecular
detail. Here we provide a structural basis for arabinose nucleotide-mediated
inhibition of human primase, the DNA-dependent RNA polymerase responsible
for initiation of DNA synthesis in DNA replication. Our data suggest
ways in which the chemical structure of fludarabine could be modified
to improve its specificity and affinity toward primase, possibly leading
to less toxic and more effective therapeutic agents.
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Holzer, Sandro; Rzechorzek, Neil J.; Short, Isobel R.; Jenkyn-Bedford, Michael; Pellegrini, Luca; Kilkenny, Mairi L. (2019). Structural Basis for Inhibition of Human Primase by
Arabinofuranosyl Nucleoside Analogues Fludarabine and Vidarabine. ACS Publications. Collection. https://doi.org/10.1021/acschembio.9b00367