Exploring the binding pockets of the DNA damage repair enzyme SNM1A through nucleobase modification

Abstract

The DNA damage repair enzyme SNM1A is a potential target for anti-cancer chemotherapy. SNM1A has a metal-containing active site that has previously been successfully targeted with nucleosides/oligonucleotides modified with metal–binding groups. Nucleosides with modifications in the 3′- and 5′-positions of the ribose ring have been shown to inhibit SNM1A. To date, modification of the nucleobase has yet to be explored for targeting SNM1A. Herein, we describe the generation of a nucleoside modified with a 5′-metal-binding group and an alkyne handle on the nucleobase. Incorporation of the alkyne handle enables functionalisation for the exploration of peripheral binding pockets. This is the first time that nucleobase modification has been explored for targeting SNM1A. However, the novel nucleoside derivative displayed no significant recognition by SNM1A.

Keywords

• Interstrand crosslink repair
• Inhibitor scaffold
• Metal-binding group
• Nucleoside modification
• SNM1A