Lysine Deacetylase Inhibitors in Parasites: Past, Present, and Future Perspectives
Lysine Deacetylase Inhibitors in Parasites: Past, Present, and Future Perspectives
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DOI：
10.1021/acs.jmedchem.6b01595
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发表时间：
2017-06-22
影响因子：
7.3
通讯作者：
Mai, Antonello
中科院分区：
文献类型：
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作者：
Hailu, Gebremedhin S.;Robaa, Dina;Mai, Antonello
目前人类寄生虫感染的治疗方法依赖于少数几种药物，其中大多数都有严重的副作用，它们的有效性正受到耐药性问题的严重影响。在全球范围内，这正在推动抗寄生虫药物的发现研究转向具有新作用机制的新药物。通过使用“药物再利用策略”，组蛋白去乙酰酶抑制剂(HDACi)目前被临床批准用于癌症，目前正在研究各种寄生虫感染。由于寄生的依赖锌和NAD(+)的HDAC在寄生虫基因表达的调控中起着关键作用，并且其中许多在不同条件下对几种寄生虫都是有利生存的，因此它们正成为新的潜在的抗寄生虫靶标。这一观点总结了针对主要人类寄生虫病(血吸虫病、疟疾、锥虫病、利什曼病和弓形虫病)的HDACi(包括I/II类HDACi和sirtuin抑制剂)的知识状况，并提供了对它们作为抗寄生剂发展所面临的主要问题的看法。
Current therapies for human parasite infections rely on a few drugs, most of which have severe side effects, and their helpfulness is being seriously compromised by the drug resistance problem. Globally, this is pushing discovery research of antiparasitic drugs toward new agents endowed with new mechanisms of action. By using a "drug repurposing strategy, histone deacetylase inhibitors (HDACi), which are presently clinically approved for cancer use, are now under investigation for various parasite infections. Because parasitic Zn2+- and NAD(+)-dependent HDACs play crucial roles in the modulation of parasite gene expression and many of them are pro-survival for several parasites under various conditions, they are now emerging as novel potential antiparasitic targets. This Perspective summarizes the state of knowledge of HDACi (both class I/II HDACi and sirtuin inhibitors) targeted to the main human parasitic diseases (schistosomiasis, malaria, trypanosomiasis, leishmaniasis, and toxoplasmosis) and provides visions into the main issues that challenge their development as antiparasitic agents.