Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential.
DNA topoisomerases are essential during transcription and replication. The therapeutic mechanism of action of topoisomerase inhibitors is enzyme poisoning rather than catalytic inhibition. Tyrosyl-DNA phosphodiesterases 1 or 2 were found as DNA repair enzymes hydrolyzing the covalent bond between the tyrosyl residue of topoisomerases I or II and the 3'- or 5'-phosphate groups in DNA, respectively. Tyrosyl-DNA phosphodiesterase 1 is a key enzyme in DNA repair machinery and a promising target for antitumor and neurodegenerative therapy. Inhibitors of tyrosyl-DNA phosphodiesterase 1 could act synergistically with topoisomerase I inhibitors and thereby potentiate the effects of topoisomerase I poisons. Tyrosyl-DNA phosphodiesterase 2 is an enzyme that specifically repairs DNA damages induced by topoisomerase II poisons and causes resistance to these drugs. Selective inhibition of tyrosyl-DNA phosphodiesterase 2 may be a novel approach to overcome intrinsic or acquired resistance to topoisomerase II-targeted drug therapy. Thus, agents that inhibit tyrosyl-DNA phosphodiesterases 1 and 2 have many applications in biochemical and physiological research and they have the potential to become anticancer and antiviral drugs. The structures, mechanism of action and therapeutic rationale of tyrosyl-DNA phosphodiesterase inhibitors and their development for combinations with topoisomerase inhibitors and DNA damaging agents are discussed.
Vorozhtsov Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 9, Novosibirsk 630090, Russian Federation. Electronic address: sergey@nioch.nsc.ru.
Sergey S
SS
Laev
Vorozhtsov Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 9, Novosibirsk 630090, Russian Federation; Novosibirsk State University, Pirogova Str. 2, Novosibirsk 630090, Russian Federation.
Nariman F
NF
Salakhutdinov
Novosibirsk State University, Pirogova Str. 2, Novosibirsk 630090, Russian Federation; Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 8, Novosibirsk 630090, Russian Federation.
Olga I
OI
Lavrik
D000951:Antigens, Neoplasm / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000075223:Poly-ADP-Ribose Binding Proteins; D013329:Structure-Activity Relationship
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D010726:Phosphodiesterase Inhibitors; D000075223:Poly-ADP-Ribose Binding Proteins; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human
Camptothecin; DNA repair; Indenoisoquinolines; Tdp1; Tdp1 inhibitors; Tdp2; Tdp2 inhibitors; Top1 inhibitors; Top2 inhibitors; Topoisomerase; Tyrosyl-DNA phosphodiesterase