标识和验证向Leishmania major的化合物Leucyl-Aminopeptidase M17的识别和验证
Mirtha E Aguado1, Sandra Carvalho2, Mario E Valdés-Tresanco3
1Center for Protein Studies, Faculty of Biology, University of Havana, 10400 Havana, Cuba.
ACS infectious diseases
|May 16, 2024
概括
新的候选药物DDD00057570和DDD00097924可以选择性地抑制Leishmania寄生虫中的M17白氨基酶 (LAP). 这些化合物有望通过向对寄生虫生存至关重要的验证酶来开发新的莱什曼病治疗方法.
科学领域:
- 寄生虫学的寄生虫学
- 药物发现 药物发现 药物发现
- 生物化学 生物化学
背景情况:
- 莱什曼病是一种被忽视的热带疾病,由于药物毒性和耐药性,治疗选择有限.
- 迫切需要针对新机制的新疗法来克服耐药性和减少毒性.
研究的目的:
- 为了在化学上验证M17氨基氨基酶 (LAP) 作为Leishmania*物种的药物标.
- 为了确定强效和选择性抑制剂的 *Leishmania* LAP.
主要方法:
- 使用RapidFire质谱测试来选LAP抑制剂.
- 在体外生长抑制试验中,使用*Leishmania*细胞内巨进行了测试.
- 用热蛋白质组分析来评估目标参与和选择性.
主要成果:
- 化合物DDD00057570和DDD00097924被确定为选择性抑制大莱什曼病的LAP.
- 这些抑制剂对*L. major*和*L. donovani*细胞内巨的*体外*生长表现出有效性.
- 过度表达*Lm*LAP降低了寄生虫的易感性,证实了目标参与,抑制剂对寄生虫LAP表现出选择性,而不是人类的ortologs.
结论:
- M17氨基氨基酶 (LAP) 是莱什曼病的验证和有前途的治疗标.
- 类似药物的小分子,如DDD00057570和DDD00097924,可以选择性地抑制*Leishmania*LAP,为治疗开发提供了潜在的新途径.
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