Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels.
Non-Native Conformational Isomers of the Catalytic Domain of PCSK9 Induce an Immune Response, Reduce Lipids and Increase LDL Receptor Levels.
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DOI：
10.3390/ijms19020640
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发表时间：
2018-02-24
影响因子：
5.6
通讯作者：
Teng BB
中科院分区：
文献类型：
--
作者：
Jiang C;Nischal H;Sun H;Li L;Cao Y;Wei P;Chang JY;Teng BB
PCSK 9（前蛋白转化酶枯草杆菌蛋白酶/kexin 9型）通过促进LDL受体降解来增加血浆胆固醇水平。目前的抗体抑制剂阻断PCSK 9和LDL受体之间的相互作用，显著降低血浆胆固醇水平，并提供有益的临床结果。为了减少PCSK 9在血浆中的作用，提出了一种新的策略，该策略将产生一组非天然的、构象改变的PCSK 9异构体（X-PCSK 9），以开发靶向天然PCSK 9的主动免疫疗法，并抑制/阻断PCSK 9与LDL受体的相互作用，从而降低血浆胆固醇水平。作者使用乱序二硫键技术生成小鼠PCSK 9催化结构域的构象改变异构体。重点是四种X-异构体的免疫反应及其对C57 BL/6 J和Apoe−/−小鼠血浆胆固醇和甘油三酯水平的影响。作者表明，在C57 BL/6 J和Apoe−/−小鼠免疫后，4种免疫原对天然PCSK 9产生了显著的免疫原性，直至第120天。这导致C57 BL/6 J小鼠的血浆胆固醇水平显著降低，Apoe−/−小鼠的水平较低。X-PCSK 9-B1处理小鼠在处理后第120天LDL受体mRNA和蛋白水平升高。因此，这项研究提供了一种新的，潜在的有希望的方法，使用长期免疫治疗高胆固醇血症。
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia.
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影响因子：
4.9
作者：
Ambuehl, Patrice M.;Tissot, Alain C.;Bachmann, Martin F.
通讯作者：
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影响因子：
158.5
作者：
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DOI：
10.1073/pnas.0903849106
发表时间：
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影响因子：
11.1
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影响因子：
6.5
作者：
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作者：
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