Departments of †Pharmacology and ‡Chemistry, University of Virginia , Charlottesville, Virginia 22908, United States.
ACS Chem Biol. 2014 Mar 21;9(3):663-72. doi: 10.1021/cb400800q. Epub 2013 Dec 23.
Cutaneous leishmaniasis remains ignored in therapeutic drug discovery programs worldwide. This is mainly because cutaneous leishmaniasis is frequently a disease of impoverished populations in countries where funds are limited for research and patient care. However, the health burden of individuals in endemic areas mandates readily available, effective, and safe treatments. Of the existing cutaneous leishmaniasis therapeutics, many are growth inhibitory to Leishmania parasites, potentially creating dormant parasite reservoirs that can be activated when host immunity is compromised, enabling the reemergence of cutaneous leishmaniasis lesions or worse spread of Leishmania parasites to other body sites. To accelerate the identification and development of novel cutaneous leishmaniasis therapeutics, we designed an integrated in vitro and in vivo screening platform that incorporated multiple Leishmania life cycles and species and probed a focused library of pharmaceutically active compounds. The objective of this phenotypic drug discovery platform was the identification and prioritization of bona fide cytotoxic chemotypes toward Leishmania parasites. We identified the Food and Drug Administration-approved drug auranofin, a known inhibitor of Leishmania promastigote growth, as a potent cytotoxic anti-leishmanial agent and inducer of apoptotic-like death in promastigotes. Significantly, the anti-leishmanial activity of auranofin transferred to cell-based amastigote assays as well as in vivo murine models. With appropriate future investigation, these data may provide the foundation for potential exploitation of gold(I)-based complexes as chemical tools or the basis of therapeutics for leishmaniasis. Thus, auranofin may represent a prototype drug that can be used to identify signaling pathways within the parasite and host cell critical for parasite growth and survival.
皮肤利什曼病在全球的治疗药物发现计划中仍然被忽视。这主要是因为皮肤利什曼病经常发生在资金有限的国家的贫困人群中，这些国家的资金有限，无法进行研究和患者护理。然而，流行地区个体的健康负担需要随时提供有效且安全的治疗方法。在现有的皮肤利什曼病治疗方法中，许多方法只是对利什曼原虫具有生长抑制作用，可能会产生潜伏的寄生虫储存库，当宿主免疫力受到损害时，这些储存库会被激活，从而使皮肤利什曼病病变重新出现，或者更糟糕的是，利什曼原虫会传播到身体其他部位。为了加速新型皮肤利什曼病治疗方法的鉴定和开发，我们设计了一个集成的体外和体内筛选平台，该平台整合了多个利什曼生命周期和物种，并探测了一个聚焦的药用活性化合物库。该表型药物发现平台的目标是鉴定和优先考虑针对利什曼原虫的真正细胞毒性化学型。我们发现，已被美国食品和药物管理局批准的药物金诺芬，一种已知的利什曼前鞭毛体生长抑制剂，是一种有效的抗利什曼原虫细胞毒性药物，并能诱导前鞭毛体发生类似凋亡的死亡。重要的是，金诺芬的抗利什曼原虫活性可以转移到基于细胞的无鞭毛体测定以及体内小鼠模型中。经过适当的进一步研究，这些数据可能为基于金（I）的配合物作为化学工具或利什曼病治疗基础的潜在开发提供依据。因此，金诺芬可能代表一种原型药物，可用于鉴定寄生虫和宿主细胞内对寄生虫生长和存活至关重要的信号通路。
