Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1

Abstract

: Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with the abasic site (AP site) base excision repair (BER) intermediate. Cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair for 8-oxoguanine DNA glycosylase 1 (OGG1). The OGG1 AP lyase activity can be increased using small molecule binders, called organocatalytic switches, to cleave the DNA backbone in a similar manner as a bifunctional DNA glycosylase. In search for novel organocatalytic switches we here identify 8-Substituted 6 thioguanines and 6-amino-pyrazolo-[3,4-d]-pyrimidine derivatives as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by β-elimination, shaping a complete, artificial AP-lyase function. These new tool compounds enhance the cellular repair of 8-oxoG and AP sites, activating a rudimentary but canonical enzymatic activity.