Morelle Christelle, Mukherjee Angana, Zhang Jiabao, Fani Fereshteh, Khandelwal Anuj, Gingras Hélène, Trottier Jocelyn, Barbier Olivier, Leprohon Philippe, Burke Martin D, Ouellette Marc
Axe des Maladies Infectieuses et Immunitaires du Centre de Recherche du CHU de Québec, Centre de Recherche en Infectiologie, and Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Québec City, Québec G1V 4G2,Canada.
Department of Chemistry, Department of Biochemistry, Arnold and Mabel Beckman Institute, Carle Illinois College of Medicine, Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
ACS Infect Dis. 2021 Aug 13;7(8):2472-2482. doi: 10.1021/acsinfecdis.1c00245. Epub 2021 Jul 20.
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 , both as free-living parasites as well as their intracellular form. Both less-toxic derivatives, similarly to AmB, target the ergosterol pathway of . 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.
用于治疗被忽视的热带病内脏利什曼病（VL）的化疗效果欠佳，仅有四种获批药物。两性霉素B（AmB）尽管有毒性，但长期以来一直是二线药物。然而，脂质体两性霉素B对VL具有高效性这一事实，使其尽管成本高昂，在许多国家仍被推进为一线药物。虽然目前有几项工作致力于寻找更便宜、更稳定的两性霉素B制剂，但另一种策略是开发毒性更低的两性霉素B衍生物。我们在此表明，两种毒性较低的两性霉素B衍生物，其在两性霉素B第16位的羧酸盐被衍生化为甲基脲（AmB-MU）或氨基脲（AmB-AU），在体外对自由生活的寄生虫及其细胞内形式均有活性。这两种毒性较低的衍生物与两性霉素B类似，均靶向寄生虫的麦角固醇途径。虽然AmB-AU衍生物在体内表现出雌性特异性肝毒性，但AmB-MU衍生物耐受性良好，且在实验性VL治疗中比两性霉素B更有效。这些研究是改进基于两性霉素B治疗一种常见寄生虫病的重要一步。
