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.

Camptothecin; DNA repair; Indenoisoquinolines; Tdp1; Tdp1 inhibitors; Tdp2; Tdp2 inhibitors; Top1 inhibitors; Top2 inhibitors; Topoisomerase; Tyrosyl-DNA phosphodiesterase.