Improving Drug Sensitivity of HIV-1 Protease Inhibitors by Restriction of Cellular Efflux System in a Fission Yeast Model.
Improving Drug Sensitivity of HIV-1 Protease Inhibitors by Restriction of Cellular Efflux System in a Fission Yeast Model.
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通过限制裂变酵母模型中细胞外排系统的限制，提高了HIV-1蛋白酶抑制剂的药物敏感性。
DOI：
10.3390/pathogens11070804
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发表时间：
2022-07-16
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裂殖酵母可以作为一种细胞系统用于高通量药物筛选。然而，通常需要更高的药物浓度才能达到与哺乳动物细胞相同的效果。我们的目标是提高药物敏感性，以便减少药物的使用。使用FDA批准的HIV-1蛋白酶抑制剂（PI）药物达芦那韦（DRV）测试了影响药物摄取的三种不同方法。首先，我们测试了没有细胞壁的原生质球是否会增加药物敏感性。其次，我们研究了电穿孔是否可以使用。虽然观察到了小的改进，但与传统方法相比，这两种方法都没有显示出DRV的EC 50值显著增加。相反，当在缺乏调节细胞外排的关键蛋白的突变株PR 836中测试DRV时，观察到EC 50显著增加。在野生型RE 294菌株和突变型PR 836菌株之间比较9种FDA批准的HIV-1 PI药物，显示药物敏感性显著增强，范围从0.56 log增加到2.48 log。因此，通过适应所述的裂殖酵母突变株来限制细胞外排增强了药物敏感性，减少了药物的使用量，并增加了未来药物发现的成功机会。
Fission yeast can be used as a cell-based system for high-throughput drug screening. However, higher drug concentrations are often needed to achieve the same effect as in mammalian cells. Our goal here was to improve drug sensitivity so reduced drugs could be used. Three different methods affecting drug uptakes were tested using an FDA-approved HIV-1 protease inhibitor (PI) drug Darunavir (DRV). First, we tested whether spheroplasts without cell walls increase the drug sensitivity. Second, we examined whether electroporation could be used. Although small improvements were observed, neither of these two methods showed significant increase in the EC50 values of DRV compared with the traditional method. In contrast, when DRV was tested in a mutant strain PR836 that lacks key proteins regulating cellular efflux, a significant increase in the EC50 was observed. A comparison of nine FDA-approved HIV-1 PI drugs between the wild-type RE294 strain and the mutant PR836 strain showed marked enhancement of the drug sensitivities ranging from an increase of 0.56 log to 2.48 logs. Therefore, restricting cellular efflux through the adaption of the described fission yeast mutant strain enhances the drug sensitivity, reduces the amount of drug used, and increases the chance of success in future drug discovery.
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