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首页> 外文期刊>Infectious Disorders - Drug Targets >Exploring DNA Topoisomerases as Targets of Novel Therapeutic Agents in the Treatment of Infectious Diseases
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Exploring DNA Topoisomerases as Targets of Novel Therapeutic Agents in the Treatment of Infectious Diseases

机译：探索以DNA拓扑异构酶为目标的新型治疗药物在传染病治疗中的作用

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DNA topoisomerases are ubiquitous enzymes needed to overcome topological problems encountered during DNA replication, transcription, recombination and maintenance of genomic stability. They have proved to be valuable targets for therapy, in part because some anti-topoisomerase agents act as poisons. Bacterial DNA gyrase and topoisomerase IV (type IIA topoisomerases) are targets of fluoroquinolones while human topoisomerase I (a type IB topoisomerase) and topoisomerase II are targets of various anticancer drugs. Bacterial type IA topoisomerase share little sequence homology to type IB or type IIA topoisomerases, but all topoisomerases have the potential of having the covalent phosphotyrosine DNA cleavage intermediate trapped by drug action. Recent studies have demonstrated that stabilization of the covalent complex formed by bacterial topoisomerase I and cleaved DNA can lead to bacterial cell death, supporting bacterial topoisomerase I as a promising target for the development of novel antibiotics. For current antibacterial therapy, the prevalence of fluoroquinolone-resistant bacterial pathogens has become a major public health concern, and efforts are directed towards identifying novel inhibitors of bacterial type IIA topoisomerases that are not affected by fluoroquinolone resistant mutations on the gyrase or topoisomerase IV genes. For anti-viral therapy, poxviruses encode their own type IB topoisomerases; these enzymes differ in drug sensitivity from human topoisomerase I. To confront potential threat of small pox as a weapon in terrorist attacks, vaccinia virus topoisomerase I has been targeted for discovery of anti-viral agents. These new developments of DNA topoisomerases as targets of novel therapeutic agents being reviewed here represent excellent opportunities for drug discovery in the treatment of infectious diseases.
机译：DNA拓扑异构酶是解决DNA复制，转录，重组和维持基因组稳定性过程中遇到的拓扑问题所需的普遍存在的酶。事实证明它们是治疗的重要靶标，部分原因是某些抗拓扑异构酶试剂可作为毒药。细菌DNA促旋酶和拓扑异构酶IV（IIA型拓扑异构酶）是氟喹诺酮类药物的靶标，而人类拓扑异构酶I（IB型拓扑异构酶）和拓扑异构酶II是各种抗癌药物的靶标。细菌IA型拓扑异构酶与IB型或IIA型拓扑异构酶几乎没有序列同源性，但是所有拓扑异构酶都有可能通过药物作用捕获共价磷酸酪氨酸DNA裂解中间体。最近的研究表明，由细菌拓扑异构酶I和裂解的DNA形成的共价复合物的稳定化可导致细菌细胞死亡，支持细菌拓扑异构酶I作为开发新型抗生素的有希望的目标。对于当前的抗菌疗法，对氟喹诺酮类耐药的细菌病原体的流行已成为主要的公共卫生问题，并且努力致力于鉴定不受旋涡酶或拓扑异构酶IV基因上的氟喹诺酮类耐药性突变影响的细菌IIA型拓扑异构酶的新型抑制剂。对于抗病毒治疗，痘病毒编码其自身的IB型拓扑异构酶。这些酶与人拓扑异构酶I在药物敏感性上有所不同。为了应对小痘病毒在恐怖袭击中的潜在威胁，牛痘病毒拓扑异构酶I已成为发现抗病毒剂的目标。 DNA拓扑异构酶的这些新发展作为本文正在审查的新型治疗剂的靶标，代表了在传染病治疗中发现药物的绝佳机会。

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