Reverse Engineering the Intracellular Self-Assembly of a Functional Mechanopharmaceutical Device.
Reverse Engineering the Intracellular Self-Assembly of a Functional Mechanopharmaceutical Device.
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DOI：
10.1038/s41598-018-21271-7
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发表时间：
2018-02-13
影响因子：
4.6
通讯作者：
Rosania GR
中科院分区：
文献类型：
--
作者：
Woldemichael T;Keswani RK;Rzeczycki PM;Murashov MD;LaLone V;Gregorka B;Swanson JA;Stringer KA;Rosania GR
弱碱性、难溶性的化学试剂可以用作构建生物体细胞内复杂分子装置的基础材料。在这里，使用实验和计算方法，我们探索了介导溶酶体离子稳态的生物学机制与弱碱性小分子结构单元（氯法齐明）在巨噬细胞溶酶体中自组装成功能性机械药物装置（细胞内晶体样药物内含物-“CLDIs”）之间的关系。物理化学方面的考虑表明，自组装机械药物装置的溶酶体内稳定性取决于弱碱性结构单元的最大pH值及其对氯化物的亲和力，这两者都与生理溶酶体微环境的pH值和氯化物含量一致。最重要的是，体外和计算机模拟研究表明，无论氯离子通道的表达水平如何，空泡ATP酶（V-ATP酶）的高表达水平都是必要的，足以解释巨噬细胞内自组装机械药物装置的细胞类型依赖性形成、稳定性和生物相容性。
Weakly basic, poorly soluble chemical agents could be exploited as building blocks for constructing sophisticated molecular devices inside the cells of living organisms. Here, using experimental and computational approaches, we probed the relationship between the biological mechanisms mediating lysosomal ion homeostasis and the self-assembly of a weakly basic small molecule building block (clofazimine) into a functional, mechanopharmaceutical device (intracellular Crystal-Like Drug Inclusions – “CLDIs”) in macrophage lysosomes. Physicochemical considerations indicate that the intralysosomal stabilization of the self-assembled mechanopharmaceutical device depends on the pHmax of the weakly basic building block and its affinity for chloride, both of which are consistent with the pH and chloride content of a physiological lysosomal microenvironment. Most importantly, in vitro and in silico studies revealed that high expression levels of the vacuolar ATPase (V-ATPase), irrespective of the expression levels of chloride channels, are necessary and sufficient to explain the cell-type dependent formation, stabilization, and biocompatibility of the self-assembled mechanopharmaceutical device within macrophages.
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影响因子：
3.7
作者：
Keswani, Rahul K.;Yoon, Gi S.;Rosania, Gus R.
通讯作者：
Rosania, Gus R.
DOI：
10.1083/jcb.121.6.1311
发表时间：
1993-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Heuser J;Zhu Q;Clarke M
通讯作者：
Clarke M
影响因子：
7.8
作者：
Gutierrez Millan, Carmen;Bax, Bridget E.;Lanao, Jose M.
通讯作者：
Lanao, Jose M.
影响因子：
3.4
作者：
Grabe, M;Wang, HY;Oster, G
通讯作者：
Oster, G
影响因子：
4.9
作者：
Baik, Jason;Stringer, Kathleen A.;Rosania, Gus R.
通讯作者：
Rosania, Gus R.