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Specific Inhibition of the Bifunctional Farnesyl/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site
Cell Chemical Biology ( IF 8.6 ) Pub Date : 2017-12-21 , DOI: 10.1016/j.chembiol.2017.11.010
Jolyn E. Gisselberg , Zachary Herrera , Lindsey M. Orchard , Manuel Llinás , Ellen Yeh

The bifunctional farnesyl/geranylgeranyl diphosphate synthase (FPPS/GGPPS) is a key branchpoint enzyme in isoprenoid biosynthesis inPlasmodium falciparum(malaria) parasites.PfFPPS/GGPPS is a validated, high-priority antimalarial drug target. Unfortunately, current bisphosphonate drugs that inhibit FPPS and GGPPS enzymes by acting as a diphosphate substrate analog show poor bioavailability and selectivity forPfFPPS/GGPPS. We identified a new non-bisphosphonate compound, MMV019313, which is highly selective forPfFPPS/GGPPS and showed no activity against human FPPS or GGPPS. Inhibition ofPfFPPS/GGPPS by MMV019313, but not bisphosphonates, was disrupted in an S228T variant, demonstrating that MMV019313 and bisphosphonates have distinct modes of inhibition. Molecular docking indicated that MMV019313 did not bind previously characterized substrate sites inPfFPPS/GGPPS. Our finding uncovers a new, selective small-molecule binding site in this important antimalarial drug target with superior druggability compared with the known inhibitor site and sets the stage for the development ofPlasmodium-specific FPPS/GGPPS inhibitors.

中文翻译:

通过新的小分子结合位点在疟原虫中的双功能法尼基/ Geranylgeranyl二磷酸合酶的特异性抑制。

双功能法呢基/香叶基香叶酸二磷酸合酶(FPPS / GGPPS)是恶性疟原虫寄生虫类异戊二烯生物合成中的关键分支酶.PfFPPS / GGPPS是一种经过验证的高优先级抗疟药靶标。不幸的是,当前的通过用作二磷酸盐底物类似物而抑制FPPS和GGPPS酶的双膦酸盐药物显示出差的生物利用度和对PfFPPS / GGPPS的选择性。我们鉴定了一种新的非双膦酸酯化合物MMV019313,它对PfFPPS / GGPPS具有高度选择性,并且对人FPPS或GGPPS没有活性。S228T变异体破坏了MMV019313对PfFPPS / GGPPS的抑制作用,但对双膦酸盐的抑制作用没有被破坏,这表明MMV019313和双膦酸盐具有不同的抑制模式。分子对接表明,MMV019313不结合PfFPPS / GGPPS中先前表征的底物位点。我们的发现在这个重要的抗疟疾药物靶标中发现了一个新的,选择性的小分子结合位点,与已知的抑制剂位点相比,具有更高的可制药性,并为开发特定于疟原虫的FPPS / GGPPS抑制剂奠定了基础。
更新日期:2018-02-15
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