Discovery of a Small Molecule PDI Inhibitor That Inhibits Reduction of HIV-1 Envelope Glycoprotein gp120
Discovery of a Small Molecule PDI Inhibitor That Inhibits Reduction of HIV-1 Envelope Glycoprotein gp120
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DOI：
10.1021/cb100387r
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发表时间：
2011-03-01
影响因子：
4
通讯作者：
Osada, Hiroyuki
中科院分区：
文献类型：
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作者：
Khan, Maola M. G.;Simizu, Siro;Osada, Hiroyuki
蛋白质二硫键异构酶（PDI）是一种多功能蛋白质。PDI通过氧化或异构化介导蛋白质正确折叠，并通过还原破坏二硫键。HIV-1进入细胞是由PDI催化的gp 120中二硫键的还原裂解促进的。PDI由于其还原活性而被认为是潜在的药物靶点。我们以高通量的方式筛选了天然产物的化学文库中的PDI特异性抑制剂，并鉴定了天然化合物Juniferdin为最有效的PDI抑制剂。合成了Juniferdin的衍生物，其中化合物13显示出与Juniferdin相当的抑制活性，但降低了细胞毒性。Juniferdin和化合物13均以剂量依赖性方式抑制PDI还原酶活性，IC 50值分别为156和167 nM。我们的研究结果还表明，Juniferdin和化合物13发挥其抑制活性，特别是对PDI，但不显着抑制同源的这个蛋白质家族。此外，我们发现这两种化合物可以抑制PDI介导的HIV-1包膜糖蛋白gp 120的还原。
Protein disulfide isomerase (PDI) is a promiscuous protein with multifunctional properties. PDI mediates proper protein folding by,oxidation or isomerization and disrupts disulfide bonds by reduction. The entry of HIV-1 into cells is facilitated by the, PDI-catalyzed reductive cleavage Of disulfide bonds in gp120. PDI is regarded as a potential drug target because of its reduction activity. We screened a chemical library of natural products for PDI-specific inhibitors in a high throughput fashion and identified the natural compound juniferdin as the most potent inhibitor of PDI. Derivatives of juniferdin were synthesized, with compound 13 showing inhibitory activities comparable to those of juniferdin but reduced cytotoxicity. Both juniferdin and compound 13 inhibited PDI reductase activity in a dose dependent manner, with IC50 values of 156 and 167 nM, respectively. Our results also indicated that juniferdin and compound 13 exert their inhibitory activities specifically on PDI but do not significantly inhibit homologues of this protein family. Moreover, we found that both compounds can inhibit PDI-mediated reduction of HIV-1 envelope glycoprotein gp120.