School of Life Sciences and Center of Novel Biomaterials, The Chinese University of Hong Kong, Shatin, Hong Kong SAR 999077, China.
Department of Applied Biology and Chemical Technology and the State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hung Hom, Hong Kong SAR 999077, China.
ACS Appl Mater Interfaces. 2024 Sep 18;16(37):49148-49163. doi: 10.1021/acsami.4c10426. Epub 2024 Sep 6.
Intracellular infections are difficult to treat, as pathogens can take advantage of intracellular hiding, evade the immune system, and persist and multiply in host cells. One such intracellular parasite, , is the causative agent of leishmaniasis, a neglected tropical disease (NTD), which disproportionately affects the world's most economically disadvantaged. Existing treatments have relied mostly on chemotherapeutic compounds that are becoming increasingly ineffective due to drug resistance, while the development of new therapeutics has been challenging due to the variety of clinical manifestations caused by different species. The antimicrobial peptide melittin has been shown to be effective in vitro against a broad spectrum of , including species that cause the most common form, cutaneous leishmaniasis, and the most deadly, visceral leishmaniasis. However, melittin's high hemolytic and cytotoxic activity toward host cells has limited its potential for clinical translation. Herein, we report a design strategy for producing a melittin-containing antileishmanial agent that not only enhances melittin's leishmanicidal potency but also abrogates its hemolytic and cytotoxic activity. This therapeutic construct can be directly produced in bacteria, significantly reducing its production cost critical for a NTD therapeutic. The designed melittin-containing fusion crystal incorporates a bioresponsive cathepsin linker that enables it to specifically release melittin in the phagolysosome of infected macrophages. Significantly, this targeted approach has been demonstrated to be efficacious in treating macrophages infected with and in cell-based models and in the corresponding cutaneous and visceral mouse models.
细胞内感染很难治疗，因为病原体可以利用细胞内隐藏、逃避免疫系统，并在宿主细胞内持续和繁殖。一种这样的细胞内寄生虫，是利什曼病（一种被忽视的热带病）的病原体，它不成比例地影响着世界上最贫困的人群。现有的治疗方法主要依赖于化疗化合物，但由于耐药性，这些化合物的效果越来越差，而由于不同物种引起的临床表现多种多样，新疗法的开发也具有挑战性。抗菌肽蜂毒素已被证明在体外对广泛的有效，包括引起最常见形式的皮肤利什曼病和最致命的内脏利什曼病的物种。然而，蜂毒素对宿主细胞的高溶血和细胞毒性活性限制了其在临床转化中的潜力。在这里，我们报告了一种生产含蜂毒素的抗利什曼原虫剂的设计策略，该策略不仅增强了蜂毒素的杀利什曼原虫活性，而且消除了其溶血和细胞毒性活性。这种治疗性构建体可以在细菌中直接产生，显著降低了生产成本，这对治疗被忽视的热带病至关重要。设计的含蜂毒素融合晶体包含一个生物响应性组织蛋白酶连接子，使其能够在感染巨噬细胞的吞噬体中特异性释放蜂毒素。重要的是，这种靶向方法已被证明在治疗细胞模型中感染的巨噬细胞和相应的皮肤和内脏小鼠模型中是有效的。
