Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential

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• 作者：Sergey S. Laev^a ; ^{sergey@nioch.nsc.ru" class="auth_mail" title="E-mail the corresponding author} ; Nariman F. Salakhutdinov^a ; ^b ; Olga I. Lavrik^b ; ^c
• 关键词：DNA repair ; Topoisomerase ; Camptothecin ; Top1 inhibitors ; Top2 inhibitors ; Tyrosyl-DNA phosphodiesterase ; Tdp1 ; Tdp2 ; Tdp1 inhibitors ; Tdp2 inhibitors ; Indenoisoquinolines
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：24
• 期：21
• 页码：5017-5027
• 全文大小：1039 K

文摘

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.