非标准氨基酸用于改善肿瘤酸性环境下pHLIP插入的pH响应。
Noncanonical amino acids to improve the pH response of pHLIP insertion at tumor acidity.
作者信息
Onyango Joab O, Chung Michael S, Eng Chee-Huat, Klees Lukas M, Langenbacher Rachel, Yao Lan, An Ming
机构信息
Department of Chemistry, State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
Department of Physics, Applied Physics and Astronomy State University of New York (SUNY), Binghamton University P. O. Box 6000, Binghamton, NY 13902 (USA).
出版信息
Angew Chem Int Ed Engl. 2015 Mar 16;54(12):3658-3663. doi: 10.1002/anie.201409770. Epub 2015 Feb 4.
The pH low insertion peptide (pHLIP) offers the potential to deliver drugs selectively to the cytoplasm of cancer cells based on tumor acidosis. The WT pHLIP inserts into membranes with a pH50 of 6.1, while most solid tumors have extracellular pH (pH(e)) of 6.5-7.0. To close this gap, a SAR study was carried out to search for pHLIP variants with improved pH response. Replacing Asp25 with α-aminoadipic acid (Aad) adjusts the pH50 to 6.74, matching average tumor acidity, and replacing Asp14 with γ-carboxyglutamic acid (Gla) increases the sharpness of pH response (transition over 0.5 instead of 1 pH unit). These effects are additive: the Asp14Gla/Asp25Aad double variant shows a pH50 of 6.79, with sharper transition than Asp25Aad. Furthermore, the advantage of the double variant over WT pHLIP in terms of cargo delivery was demonstrated in turn-on fluorescence assays and anti-proliferation studies (using paclitaxel as cargo) in A549 lung cancer cells at pH 6.6.
pH低插入肽（pHLIP）具有基于肿瘤酸中毒将药物选择性递送至癌细胞细胞质的潜力。野生型pHLIP在pH50为6.1时插入膜中，而大多数实体瘤的细胞外pH（pH(e)）为6.5 - 7.0。为了缩小这一差距，开展了一项构效关系（SAR）研究，以寻找具有改善pH响应的pHLIP变体。用α-氨基己二酸（Aad）取代Asp25可将pH50调整至6.74，与平均肿瘤酸度相匹配，用γ-羧基谷氨酸（Gla）取代Asp14可提高pH响应的敏锐度（转变超过0.5个pH单位而非1个pH单位）。这些效应是累加的：Asp14Gla/Asp25Aad双变体的pH50为6.79，其转变比Asp25Aad更敏锐。此外，在pH 6.6的A549肺癌细胞中进行的开启式荧光测定和抗增殖研究（使用紫杉醇作为货物）中，依次证明了双变体在货物递送方面相对于野生型pHLIP的优势。
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