HMG-CoA Reductase Inhibitors as Drug Leads against Naegleria fowleri.,ACS Chemical Neuroscience

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HMG-CoA Reductase Inhibitors as Drug Leads against Naegleria fowleri.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-09-03 , DOI: 10.1021/acschemneuro.0c00428
Hye Jee Hahn ₁ , Ruben Abagyan ₁ , Larissa M Podust ₁ , Shantanu Roy ₂ , Ibne Karim M Ali ₂ , Anjan Debnath ₁

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Primary amebic meningoencephalitis (PAM), caused by the free-living ameba Naegleria fowleri, has a fatality rate of over 97%. Treatment of PAM relies on amphotericin B in combination with other drugs, but few patients have survived with the existing drug treatment regimens. Therefore, development of effective drugs is a critical unmet need to avert deaths from PAM. Since ergosterol is one of the major sterols in the membrane of N. fowleri, disruption of isoprenoid and sterol biosynthesis by small-molecule inhibitors may be an effective intervention strategy against N. fowleri. The genome of N. fowleri contains a gene encoding HMG-CoA reductase (HMGR); the catalytic domains of human and N. fowleri HMGR share <60% sequence identity with only two amino acid substitutions in the active site of the enzyme. Considering the similarity of human and N. fowleri HMGR, we tested well-tolerated and widely used HMGR inhibitors, known as cholesterol-lowering statins, against N. fowleri. We identified blood-brain-barrier-permeable pitavastatin as a potent amebicidal agent against the U.S., Australian, and European strains of N. fowleri. Pitavastatin was equipotent to amphotericin B against the European strain of N. fowleri; it killed about 80% of trophozoites within 16 h of drug exposure. Pretreatment of trophozoites with mevalonate, the product of HMGR, rescued N. fowleri from inhibitory effects of statins, demonstrating that HMGR of N. fowleri is the target of statins. Because of the good safety profile and availability for both adult and pediatric uses, consideration should be given to repurposing the fast-acting pitavastatin for the treatment of PAM.

中文翻译：

HMG-CoA 还原酶抑制剂作为抗福氏奈格氏菌的药物。

由自由生活的福氏阿米巴原虫引起的原发性阿米巴脑膜脑炎 (PAM)的致死率超过 97%。PAM 的治疗依赖于两性霉素 B 联合其他药物，但很少有患者在现有的药物治疗方案下存活。因此，开发有效药物是避免 PAM 死亡的关键未满足需求。由于麦角甾醇是福氏猪笼草细胞膜中的主要甾醇之一，小分子抑制剂对类异戊二烯和甾醇生物合成的破坏可能是对福氏猪笼草的有效干预策略。N. fowleri的基因组包含一个编码 HMG-CoA 还原酶 (HMGR) 的基因；人和N. fowleri的催化域HMGR 具有 <60% 的序列同一性，在酶的活性位点中只有两个氨基酸取代。考虑到人类和福氏猪笼草HMGR的相似性，我们测试了耐受性良好且广泛使用的 HMGR 抑制剂（称为降胆固醇他汀类药物）对抗福氏猪笼草。我们发现血脑屏障可渗透的匹伐他汀是一种有效的抗阿米巴剂，可以对抗美国、澳大利亚和欧洲的福氏猪瘟。匹伐他汀与两性霉素 B 对欧洲福氏猪笼草菌株具有同等效力；它在接触药物 16 小时内杀死了约 80% 的滋养体。用 HMGR 的产物甲羟戊酸对滋养体进行预处理，拯救了N. fowleri来自他汀类药物的抑制作用，证明N. fowleri 的HMGR是他汀类药物的目标。由于成人和儿童使用的良好安全性和可用性，应考虑重新利用速效匹伐他汀治疗 PAM。

更新日期：2020-10-07

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