Structural basis for inhibition of human primase by arabinofuranosyl nucleoside analogues fludarabine and vidarabine

DOI: 10.1021/acschembio.9b00367

Authors: Sandro Holzer (University of Cambridge) , Neil J. Rzechorzek (University of Cambridge) , Isobel R. Short (University of Cambridge) , Michael Jenkyn-bedford (University of Cambridge) , Luca Pellegrini (University of Cambridge) , Mairi Kilkenny (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Chemical Biology

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 9537

Abstract: 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 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 towards primase, possibly leading to less toxic and more effective therapeutic agents.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Other Facilities: SOLEIL