Hybrid Cyclic-Linear Cell-Penetrating Peptides Containing Alternative Positively Charged and Hydrophobic Residues as Molecular Transporters,Molecular Pharmaceutics

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Hybrid Cyclic-Linear Cell-Penetrating Peptides Containing Alternative Positively Charged and Hydrophobic Residues as Molecular Transporters
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2021-09-07 , DOI: 10.1021/acs.molpharmaceut.1c00594
Sorour Khayyatnejad Shoushtari ₁ , Khalid Zoghebi _{1,

2} , Muhammad Imran Sajid _{1,

3} , Rakesh Kumar Tiwari ₁ , Keykavous Parang ₁

Affiliation

The cell membrane properties create a significant obstacle in intracellular delivery of cell-impermeable and negatively charged molecules. Herein, we report the synthesis and biological evaluation of a novel series of hybrid cyclic-linear peptides containing alternative positive and hydrophobic amino acids on the ring and side chain [(RW)₅]K(RW)_X (X = 1–5) to compare their molecular transporter efficiency. The peptides were synthesized through Fmoc solid-phase peptide synthesis. In vitro cytotoxicity of the peptides showed that the peptides did not exhibit any significant cytotoxicity at the concentration of 10 μM in human leukemia carcinoma cell line (CCRF-CEM), human ovarian adenocarcinoma cells (SK-OV-3), human epithelial embryonic kidney healthy (HEK-293), and human epithelial mammary gland adenocarcinoma cells (MDA-MB-231) after 3 h incubation. The cellular uptake of a fluorescence-labeled phosphopeptide (F′-GpYEEI) and anti-human immunodeficiency virus (HIV) drugs (lamivudine (F′-3TC), emtricitabine (F′-FTC), Stavudine (F′-d4T)), where F′ is carboxyfluorescein, was measured in the presence of the peptides in CCRF-CEM and SK-OV-3 cells. Among all peptides, [(RW)₅K](RW)₅ (10 μM) was the most efficient transporter that improved the cellular uptake of F′-GpYEEI (2 μM) by 18- and 11-fold in CCRF-CEM and SK-OV-3, respectively, compared with F′-GpYEEI alone. Fluorescence-activated cell sorting (FACS) analysis results indicated that the cellular uptake of fluorescence-labeled peptide (F′-[(RW)₅K](RW)₅) was only partially inhibited by chlorpromazine as an endocytosis inhibitor after 3 h incubation in MDA-MB-231 cells. These data suggest the potential of this series of hybrid cyclic-linear peptides as cell-penetrating peptides and molecular transporters.

中文翻译：

含有可替代的带正电荷和疏水残基作为分子转运蛋白的混合环状线性细胞穿透肽

细胞膜特性在细胞内传递细胞不可渗透和带负电荷的分子方面产生了重大障碍。在此，我们报告了一系列新型混合环状线性肽的合成和生物学评价，这些肽在环和侧链上含有替代的正和疏水氨基酸 [(RW) ₅ ]K(RW) _X ( X= 1-5) 比较它们的分子转运蛋白效率。通过Fmoc固相肽合成法合成肽。肽的体外细胞毒性表明，10 μM 浓度的肽在人白血病癌细胞系 (CCRF-CEM)、人卵巢腺癌细胞 (SK-OV-3)、人上皮胚胎肾中没有表现出任何显着的细胞毒性健康（HEK-293）和人上皮乳腺腺癌细胞（MDA-MB-231）孵育3小时后。荧光标记的磷酸肽 (F'-GpYEEI) 和抗人类免疫缺陷病毒 (HIV) 药物（拉米夫定 (F'-3TC)、恩曲他滨 (F'-FTC)、司他夫定 (F'-d4T)）的细胞摄取，其中 F' 是羧基荧光素，在 CCRF-CEM 和 SK-OV-3 细胞中存在肽的情况下测量。在所有肽中，[(RW)₅ K](RW) ₅ (10 μM) 是最有效的转运蛋白，在 CCRF-CEM 和 SK-OV-3 中分别将 F'-GpYEEI (2 μM) 的细胞摄取提高了 18 倍和 11 倍，与单独的 F'-GpYEEI 相比。荧光激活细胞分选 (FACS) 分析结果表明，在孵育 3 小时后，氯丙嗪作为内吞作用抑制剂仅部分抑制荧光标记肽 (F'-[(RW) ₅ K](RW) ₅ ) 的细胞摄取在 MDA-MB-231 细胞中。这些数据表明这一系列混合环状线性肽作为细胞穿透肽和分子转运蛋白的潜力。

更新日期：2021-10-04

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