Well-Tolerated Amphotericin B Derivatives That Effectively Treat Visceral Leishmaniasis,ACS Infectious Diseases

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Well-Tolerated Amphotericin B Derivatives That Effectively Treat Visceral Leishmaniasis
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2021-07-20 , DOI: 10.1021/acsinfecdis.1c00245
Christelle Morelle ₁ , Angana Mukherjee ₁ , Jiabao Zhang ₂ , Fereshteh Fani ₁ , Anuj Khandelwal ₂ , Hélène Gingras ₁ , Jocelyn Trottier ₃ , Olivier Barbier ₃ , Philippe Leprohon ₁ , Martin D Burke ₂ , Marc Ouellette ₁

Affiliation

Chemotherapy against the neglected tropical disease visceral leishmaniasis (VL) is suboptimal with only four licensed drugs. Amphotericin B (AmB), despite its toxicity, remained a second line drug for a long time. However, the demonstration that liposomal AmB is highly effective against VL propelled it, despite its cost, to a first line drug in many countries. While several ongoing efforts are aiming at finding cheaper and stable AmB-formulations, an alternative strategy is the development of less-toxic AmB derivatives. We show here that two less-toxic AmB derivatives with the carboxylate at position 16 of AmB derivatized to a methyl urea (AmB-MU) or amino urea (AmB-AU) are active in vitro against Leishmania donovani, both as free-living parasites as well as their intracellular form. Both less-toxic derivatives, similarly to AmB, target the ergosterol pathway of L. donovani. While the AmB-AU derivative showed female-specific liver toxicity in vivo, the AmB-MU derivative was well-tolerated and more effective than AmB against experimental VL. These studies are an important step for improving AmB-based therapy against a prevalent parasitic disease.

中文翻译：

有效治疗内脏利什曼病的耐受性良好的两性霉素 B 衍生物

针对被忽视的热带病内脏利什曼病 (VL) 的化疗效果不佳，只有四种获得许可的药物。两性霉素 B (AmB) 尽管具有毒性，但长期以来一直是二线药物。然而，脂质体 AmB 对 VL 非常有效的证明推动它成为许多国家的一线药物，尽管其成本很高。虽然一些正在进行的努力旨在寻找更便宜和稳定的 AmB 制剂，但另一种策略是开发毒性较小的 AmB 衍生物。我们在此展示了两种毒性较低的 AmB 衍生物，其中 AmB 的 16 位羧酸盐衍生为甲基脲 (AmB-MU) 或氨基脲 (AmB-AU) 在体外对多诺瓦尼利什曼原虫具有活性，既是自由生活的寄生虫，也是它们的细胞内形式。与 AmB 类似，这两种毒性较小的衍生物都针对多诺瓦尼乳杆菌的麦角甾醇途径。虽然 AmB-AU 衍生物在体内表现出女性特异性肝毒性，但 AmB-MU 衍生物具有良好的耐受性，并且比 AmB 对实验性 VL 更有效。这些研究是改进基于 AmB 的针对流行寄生虫病的治疗的重要一步。

更新日期：2021-08-13

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