PT  - JOURNAL ARTICLE
AU  - Sandro Holzer
AU  - Neil J. Rzechorzek
AU  - Isobel R. Short
AU  - Michael Jenkyn-Bedford
AU  - Luca Pellegrini
AU  - Mairi L. Kilkenny
TI  - Structural basis for inhibition of human primase by arabinofuranosyl nucleoside analogues Fludarabine and Vidarabine
AID  - 10.1101/605279
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 605279
4099  - http://biorxiv.org/content/early/2019/04/11/605279.short
4100  - http://biorxiv.org/content/early/2019/04/11/605279.full
AB  - 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 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 inhibition by arabinose nucleotides 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 towards primase, possibly leading to less toxic and more effective therapeutic agents.