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N-METHYLPURINE DNA GLYCOSYLASE AND 8-OXOGUANINE DNA GLYCOSYLASE METABOLIZE THE ANTIVIRAL NUCLEOSIDE 2-BROMO-5,6-DICHLORO-1-(ß-D-RIBOFURANOSYL)BENZIMIDAZOLE

Departments of Pharmaceutical Sciences (P.L.L., C.P.L., X.S., G.L.A.) and Medicinal Chemistry (L.B.T., J.C.D.), College of Pharmacy, and Department of Biologic and Materials Sciences (J.C.D.), School of Dentistry, University of Michigan, Ann Arbor, Michigan; and Welsh School of Pharmacy (A.B.), Cardiff University, Wales, United Kingdom

The rapid in vivo degradation of the potent human cytomegalovirus inhibitor 2-bromo-5,6-dichloro-1-(ß-D-ribofuranosyl)benzimidazole (BDCRB) compared with a structural L-analog, maribavir (5,6-dichloro-2-(isopropylamino)-1-ß-L-ribofuranosyl-1H-benzimidazole), has been attributed to selective glycosidic bond cleavage. An enzyme responsible for this selective BDCRB degradation, however, has not been identified. Here, we report the identification of two enzymes, 8-oxoguanine DNA glycosylase (OGG1) and N-methylpurine DNA glycosylase (MPG), that catalyze N-glycosidic bond cleavage of BDCRB and its 2-chloro homolog, 2,5,6-trichloro-1-(ß-D-ribofuranosyl)benzimidazole, but not maribavir. To our knowledge, this is the first demonstration that free nucleosides are substrates of OGG1 and MPG. To understand how these enzymes might process BDCRB, docking and molecular dynamics simulations were performed with the native human OGG1 crystal coordinates. These studies showed that OGG1 was not able to bind a negative control, guanosine, yet BDCRB and maribavir were stabilized through interactions with various binding site residues, including Phe³¹⁹, His²⁷⁰, Ser³²⁰, and Asn¹⁴⁹. Only BDCRB, however, achieved orientations whereby its anomeric carbon, C1', could undergo nucleophilic attack by the putative catalytic residue, Lys²⁴⁹. Thus, in silico observations were in perfect agreement with experimental observations. These findings implicate DNA glycosylases in drug metabolism.