Cell-penetrating peptides as transporters for morpholino oligomers: effects of amino acid composition on intracellular delivery and cytotoxicity.
Cell-penetrating peptides as transporters for morpholino oligomers: effects of amino acid composition on intracellular delivery and cytotoxicity.
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细胞穿透肽作为形态寡聚物的转运蛋白：氨基酸组成对细胞内递送和细胞毒性的影响。
DOI：
10.1093/nar/gkm478
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发表时间：
2007
影响因子：
14.9
通讯作者：
Moulton HM
中科院分区：
文献类型：
--
作者：
Wu RP;Youngblood DS;Hassinger JN;Lovejoy CE;Nelson MH;Iversen PL;Moulton HM
富含精氨酸的细胞穿透肽（CPPs）是一种很有前途的反义吗啉寡聚体（PMO）细胞内转运载体。在这里，我们确定了L-精氨酸、D-精氨酸和非α氨基酸对24种CPP− PMO的细胞摄取、剪接校正活性、细胞毒性和血清结合的影响。将6-氨基己酸（X）或β-丙氨酸（B）残基插入寡聚精氨酸R8中降低了细胞摄取，但增加了所得化合物的剪接校正活性，其中含有更多X残基的序列增加更大。对于高达10 μM的任何缀合物，均未观察到细胞毒性。在高达60 μM时，仅具有105个X的缀合物表现出时间和浓度依赖性毒性。用D-精氨酸取代L-精氨酸不会增加摄取或剪接校正活性。高浓度血清显著降低寡聚精氨酸偶联物的摄取和剪接校正活性，但对含X或B的偶联物的影响较小。总之，X/B与寡聚精氨酸的结合增强了CPP−PMO的反义活性和血清结合特性。含X/B偶联物的毒性受X的数目、处理时间和浓度的影响。通过优化R、D-R、X和B残基的位置和数目，可以设计出活性更高、稳定性更好、毒性更低的CPP。
Arginine-rich cell-penetrating peptides (CPPs) are promising transporters for intracellular delivery of antisense morpholino oligomers (PMO). Here, we determined the effect of L-arginine, D-arginine and non-α amino acids on cellular uptake, splice-correction activity, cellular toxicity and serum binding for 24 CPP−PMOs. Insertion of 6-aminohexanoic acid (X) or β-alanine (B) residues into oligoarginine R8 decreased the cellular uptake but increased the splice-correction activity of the resulting compound, with a greater increase for the sequences containing more X residues. Cellular toxicity was not observed for any of the conjugates up to 10 μM. Up to 60 μM, only the conjugates with ⩾ 5 Xs exhibited time- and concentration-dependent toxicity. Substitution of L-arginine with D-arginine did not increase uptake or splice-correction activity. High concentration of serum significantly decreased the uptake and splice-correction activity of oligoarginine conjugates, but had much less effect on the conjugates containing X or B. In summary, incorporation of X/B into oligoarginine enhanced the antisense activity and serum-binding profile of CPP−PMO. Toxicity of X/B-containing conjugates was affected by the number of Xs, treatment time and concentration. More active, stable and less toxic CPPs can be designed by optimizing the position and number of R, D-R, X and B residues.
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影响因子：
5.1
作者：
McClorey, G.;Moulton, H. M.;Wilton, S. D.
通讯作者：
Wilton, S. D.
DOI：
10.1089/108729003764097322
发表时间：
2003-02-01
期刊：
ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT
影响因子：
--
作者：
Moulton, HM;Hase, MC;Iversen, PL
通讯作者：
Iversen, PL
影响因子：
2.8
作者：
McClorey, G.;Fall, A. M.;Wilton, S. D.
通讯作者：
Wilton, S. D.
影响因子：
5.4
作者：
Deas, TS;Binduga-Gajewska, I;Shi, PY
通讯作者：
Shi, PY
影响因子：
2.9
作者：
Kang, SH;Cho, MJ;Kole, R
通讯作者：
Kole, R