Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin release in mice.
Reverse-QTY code design of active human serum albumin self-assembled amphiphilic nanoparticles for effective anti-tumor drug doxorubicin release in mice.
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DOI：
10.1073/pnas.2220173120
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发表时间：
2023-05-23
影响因子：
11.1
通讯作者：
Zhang, Shuguang
中科院分区：
文献类型：
--
作者：
Meng, Run;Hao, Shilei;Sun, Changfa;Hou, Zongkun;Hou, Yao;Wang, Lili;Deng, Peiying;Deng, Jia;Yang, Yaying;Xia, Haijian;Wang, Bochu;Qing, Rui;Zhang, Shuguang
关键词：
QTY编码已成功地用于显著提高水不溶性整合跨膜蛋白的溶解度。它们包括G蛋白偶联受体、细胞因子受体、葡萄糖转运蛋白和溶质载体转运蛋白，其通过用谷氨酰胺（Q）、苏氨酸（T）和酪氨酸（Y）系统地替换跨膜结构域中的疏水性亮氨酸（L）、缬氨酸（V）、异亮氨酸（I）和苯丙氨酸（F）来实现。在这里，我们将QTY代码反转为反向QTY（rQTY）代码，以提高人血清白蛋白上特定α-螺旋的疏水性，用于自组装成定义明确的纳米颗粒。rQTY编码对于设计高水溶性蛋白质的特异性疏水结构域具有重要意义，可用于设计其自组装体以实现药物的包封、受体介导的药物缓释和靶向跨膜转运等多种应用。人血清白蛋白（HSA）是一种高度水溶性蛋白质，具有67%的α-螺旋含量和三个不同的结构域（I，II和III）。HSA在药物递送中具有增强的渗透性和保留效果，提供了很大的希望。但在药物包埋或偶联过程中，蛋白质变性会阻碍药物的转运，导致药物的细胞转运途径不同，生物活性降低。在这里，我们报告使用一种蛋白质设计方法命名为反向定量（rQTY）代码，将特定的亲水性α-螺旋疏水α-螺旋。所设计的HSA经历具有高度生物活性的有序纳米颗粒的自组装。HSA的螺旋B亚结构域中的亲水性氨基酸天冬酰胺（N）、谷氨酰胺（Q）、苏氨酸（T）和酪氨酸（Y）被疏水性亮氨酸（L）、缬氨酸（V）和苯丙氨酸（F）系统地取代。HSArQTY纳米颗粒通过细胞膜白蛋白结合蛋白GP 60或分泌蛋白（分泌蛋白，酸性且富含半胱氨酸）介导的途径表现出有效的细胞内化。设计的HSArQTY变体显示出与变性HSA纳米颗粒相比的上级生物活性，包括：i）药物阿霉素的包封，ii）受体介导的细胞转运，iii）肿瘤细胞靶向，以及iv）抗肿瘤效率。与抗溶剂沉淀法制备的白蛋白纳米粒相比，HSArQTY纳米粒具有上级肿瘤靶向性和抗肿瘤疗效。我们认为，rQTY代码是一个强大的平台，具有明确定义的结合界面的功能性亲水蛋白质的特异性疏水修饰。
QTY code has been successfully used to significantly improve the solubility of water-insoluble integral transmembrane proteins. They include G protein-coupled receptors, cytokine receptors, glucose transporters, and solute carrier transporters through systematically replacing the hydrophobic leucine (L), valine (V), isoleucine (I), and phenylalanine (F) in the transmembrane domains by glutamine (Q), threonine (T), and tyrosine (Y). Here we reverse the QTY code as the reverse-QTY (rQTY) code to improve the hydrophobicity of the specific alpha-helices on human serum albumin for self-assembly into well-defined nanoparticles. The rQTY code has significant implications for design of specific hydrophobic domain of highly water-soluble proteins to design their self-assembly for diverse applications including encapsulate hydrophobic drugs, receptor-mediated sustained drug release and target the drug transport across cell membrane. Human serum albumin (HSA) is a highly water-soluble protein with 67% alpha-helix content and three distinct domains (I, II, and III). HSA offers a great promise in drug delivery with enhanced permeability and retention effect. But it is hindered by protein denaturation during drug entrapment or conjugation that result in distinct cellular transport pathways and reduction of biological activities. Here we report using a protein design approach named reverse-QTY (rQTY) code to convert specific hydrophilic alpha-helices to hydrophobic to alpha-helices. The designed HSA undergo self-assembly of well-ordered nanoparticles with highly biological actives. The hydrophilic amino acids, asparagine (N), glutamine (Q), threonine (T), and tyrosine (Y) in the helical B-subdomains of HSA were systematically replaced by hydrophobic leucine (L), valine (V), and phenylalanine (F). HSArQTY nanoparticles exhibited efficient cellular internalization through the cell membrane albumin binding protein GP60, or SPARC (secreted protein, acidic and rich in cysteine)-mediated pathways. The designed HSArQTY variants displayed superior biological activities including: i) encapsulation of drug doxorubicin, ii) receptor-mediated cellular transport, iii) tumor cell targeting, and iv) antitumor efficiency compare to denatured HSA nanoparticles. HSArQTY nanoparticles provided superior tumor targeting and antitumor therapeutic effects compared to the albumin nanoparticles fabricated by antisolvent precipitation method. We believe that the rQTY code is a robust platform for specific hydrophobic modification of functional hydrophilic proteins with clear-defined binding interfaces.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
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Hassabis D
影响因子：
10.8
作者：
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通讯作者：
Mitragotri, Samir
影响因子：
11.5
作者：
Desai, N;Trieu, V;Soon-Shiong, P
通讯作者：
Soon-Shiong, P
影响因子：
16.6
作者：
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影响因子：
29.4
作者：
Cen, Dong;Ge, Qiwei;Cai, Xiujun
通讯作者：
Cai, Xiujun