Boulet Coralie, Siddiqui Ghizal, Gaynor Taylah L, Doerig Christian, Creek Darren J, Carvalho Teresa G
Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC 3086, Australia.
Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
Microorganisms. 2022 Apr 15;10(4):824. doi: 10.3390/microorganisms10040824.
The development of antimalarial drug resistance is an ongoing problem threatening progress towards the elimination of malaria, and antimalarial treatments are urgently needed for drug-resistant malaria infections. Host-directed therapies (HDT) represent an attractive strategy for the development of new antimalarials with untapped targets and low propensity for resistance. In addition, drug repurposing in the context of HDT can lead to a substantial decrease in the time and resources required to develop novel antimalarials. Host BCL-x is a target in anti-cancer therapy and is essential for the development of numerous intracellular pathogens. We hypothesised that red blood cell (RBC) BCL-x is essential for development and tested this hypothesis using six BCL-x inhibitors, including one FDA-approved compound. All BCL-x inhibitors tested impaired proliferation of 3D7 parasites at low micromolar or sub-micromolar concentrations. Western blot analysis of infected cell fractions and immunofluorescence microscopy assays revealed that host BCL-x is relocated from the RBC cytoplasm to the vicinity of the parasite upon infection. Further, immunoprecipitation of BCL-x coupled with mass spectrometry analysis identified that BCL-x forms unique molecular complexes with human μ-calpain in uninfected RBCs, and with human SHOC2 in infected RBCs. These results provide interesting perspectives for the development of host-directed antimalarial therapies and drug repurposing efforts.
抗疟药物耐药性的发展是一个持续存在的问题，威胁着疟疾消除工作的进展，因此迫切需要针对耐药性疟疾感染的抗疟治疗方法。宿主导向疗法（HDT）是一种颇具吸引力的策略，可用于开发具有尚未开发靶点且耐药倾向低的新型抗疟药物。此外，在HDT背景下进行药物重新利用可大幅减少开发新型抗疟药物所需的时间和资源。宿主BCL-x是抗癌治疗的一个靶点，对多种细胞内病原体的发育至关重要。我们假设红细胞（RBC）中的BCL-x对疟原虫发育至关重要，并使用六种BCL-x抑制剂（包括一种FDA批准的化合物）对这一假设进行了验证。所有测试的BCL-x抑制剂在低微摩尔或亚微摩尔浓度下均会损害3D7疟原虫的增殖。对感染细胞组分的蛋白质免疫印迹分析和免疫荧光显微镜检测显示，感染后宿主BCL-x从红细胞胞质转移至疟原虫附近。此外，BCL-x的免疫沉淀结合质谱分析表明，在未感染的红细胞中，BCL-x与人类μ-钙蛋白酶形成独特的分子复合物，而在感染的红细胞中，BCL-x与人类SHOC2形成独特的分子复合物。这些结果为宿主导向的抗疟治疗和药物重新利用研究提供了有趣的视角。
