Discovery of pH-Selective Marine and Plant Natural Product Inhibitors of Cathepsin B Revealed by Screening at Acidic and Neutral pH Conditions.
Discovery of pH-Selective Marine and Plant Natural Product Inhibitors of Cathepsin B Revealed by Screening at Acidic and Neutral pH Conditions.
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DOI：
10.1021/acsomega.2c02287
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发表时间：
2022-07-26
期刊：
影响因子：
4.1
通讯作者：
Hook, Vivian
中科院分区：
文献类型：
--
作者：
Phan, Von V.;Mosier, Charles;Yoon, Michael C.;Glukhov, Evgenia;Caffrey, Conor R.;O'Donoghue, Anthony J.;Gerwick, William H.;Hook, Vivian
组织蛋白酶B的调节失调，涉及酶从酸性pH溶酶体到中性pH胞浆的移位，随后引发细胞死亡和炎症，在许多大脑疾病中发生。溶酶体的酸性pH(4.6)与胞浆中性pH(7.2)之间的巨大差异表明，在不同的pH条件下的筛选可以识别组织蛋白酶B的pH选择性调节剂。因此，在组织蛋白酶B的测定中，在pH 4.6和pH 7.2的条件下筛选了一批纯海洋和植物天然产物(NP)化合物，从而在酸性pH下鉴定了GER-12(Crossbyano B)和GER-24((7Z，9Z，12Z)-octadeca-7，9，12-Trien-5-ynoic acid)海洋NP抑制剂。GER-12对组织蛋白酶B有明显的可逆抑制作用，其IC50值为3μM，GER-24的IC50值为16μM，是一种不可逆的抑制物。这些结果表明，在不同的生物pH条件下进行NP筛选可以鉴定出pH选择性的组织蛋白酶B调节剂。这些发现表明，在分子探针和药物发现的筛选工作中，可能会考虑疾病过程中靶点的生物pH环境。
Dysregulation of cathepsin B, which involves the translocation of the enzyme from acidic pH lysosomes to the neutral pH cytosol, followed by the initiation of cell death and inflammation, occurs in numerous brain disorders. The wide difference in the acidic pH (4.6) of lysosomes compared to the neutral pH (7.2) of the cytosol suggests that screening at different pH conditions may identify pH-selective modulators of cathepsin B. Therefore, a collection of pure marine and plant natural product (NP) compounds, with synthetic compounds, was screened at pH 4.6 and pH 7.2 in cathepsin B assays, which led to the identification of GER-12 (Crossbyanol B) and GER-24 ((7Z,9Z,12Z)-octadeca-7,9,12-trien-5-ynoic acid) marine NP inhibitors at acidic pH but not at neutral pH. GER-12 was effective for the reversible inhibition of cathepsin B, with an IC50 of 3 μM. GER-24 had an IC50 of 16 μM and was found to be an irreversible inhibitor. These results show that NP screening at distinct biological pH conditions can lead to the identification of pH-selective cathepsin B modulators. These findings suggest that screening efforts for molecular probes and drug discovery may consider the biological pH environment of the target in the disease process.
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影响因子：
7.3
作者：
Amaral EP;Riteau N;Moayeri M;Maier N;Mayer-Barber KD;Pereira RM;Lage SL;Kubler A;Bishai WR;D'Império-Lima MR;Sher A;Andrade BB
通讯作者：
Andrade BB
影响因子：
3.4
作者：
Hook G;Jacobsen JS;Grabstein K;Kindy M;Hook V
通讯作者：
Hook V
影响因子：
3.7
作者：
Rajamäki K;Lappalainen J;Oörni K;Välimäki E;Matikainen S;Kovanen PT;Eklund KK
通讯作者：
Eklund KK
DOI：
10.1111/bpa.13071
发表时间：
2022-09
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
通讯作者：
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影响因子：
2.9
作者：
Yoon, Michael C.;Christy, Mitchell P.;Phan, Von V.;Gerwick, William H.;Hook, Gregory;O'Donoghue, Anthony J.;Hook, Vivian
通讯作者：
Hook, Vivian