Improving Drug Sensitivity of HIV-1 Protease Inhibitors by Restriction of Cellular Efflux System in a Fission Yeast Model

被引:2
|
作者
Zhang, Jiantao [1 ]
Li, Qi [1 ]
Kawashima, Shigehiro A. [2 ]
Nasr, Mohamed [3 ]
Xue, Fengtian [4 ]
Zhao, Richard Y. [1 ,5 ,6 ,7 ,8 ]
机构
[1] Univ Maryland, Dept Pathol, Sch Med, Baltimore, MD 21201 USA
[2] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan
[3] NIAID, Drug Dev & Clin Sci Branch, Div AIDS, NIH, Bethesda, MD 20892 USA
[4] Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, Baltimore, MD 21201 USA
[5] Univ Maryland, Dept Microbiol Immunol, Sch Med, Baltimore, MD 21201 USA
[6] Univ Maryland, Inst Human Virol, Sch Med, Baltimore, MD 21201 USA
[7] Univ Maryland, Inst Global Hlth, Sch Med, Baltimore, MD 21201 USA
[8] VA Maryland Hlth Care Syst, Res & Dev Serv, Baltimore, MD 21201 USA
来源
PATHOGENS | 2022年 / 11卷 / 07期
关键词
fission yeast (Schizosaccharomyces pombe); small molecule drug uptake; spheroplasts; electroporation; drug efflux pumps; ABC and MFS transporters; human immunodeficiency virus type 1 (HIV-1); protease (PR); protease inhibitor (PI) drugs; SCHIZOSACCHAROMYCES-POMBE; GENE; EXPRESSION; DELIVERY; ELECTROPORATION; TRANSPORTERS; EFFICIENCY;
D O I
10.3390/pathogens11070804
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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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页数:16
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