Modified Linear Peptides Effectively Silence STAT-3 in Breast Cancer and Ovarian Cancer Cell Lines.
Modified Linear Peptides Effectively Silence STAT-3 in Breast Cancer and Ovarian Cancer Cell Lines.
复制标题
DOI：
10.3390/pharmaceutics15020666
复制
发表时间：
2023-02-16
期刊：
影响因子：
5.4
通讯作者：
Montazeri Aliabadi H
中科院分区：
文献类型：
--
作者：
Mandal D;Lohan S;Sajid MI;Alhazza A;Tiwari RK;Parang K;Montazeri Aliabadi H
RNA干扰（RNAi）作为一种强大的工具，由于其能够干扰mRNA和蛋白质的产生而引起了广泛的关注。然而，在RNAi治疗中设计一种安全有效的递送系统仍然具有挑战性。在此，我们设计并合成了几种含有色氨酸(W)和精氨酸(R)残基的线性肽，由β-丙氨酸（βA）间隔物分隔，并连接到亲脂性脂肪酰基链，胆固醇或PEG。肽骨架序列为Ac-C-βA-βA- w4 -βA-βA- r4 - co - nh2和Ac-K-βA-βA- w4 -βA-βA- r4 - co - nh2，仅n端氨基酸不同。第一个序列的半胱氨酸侧链用于与PEG2000和PEG550的偶联。或者，第二序列赖氨酸侧链用于与胆固醇或油酸偶联。我们假设两亲性肽和最佳的脂肪酰基链或PEG可以通过补充每个结构成分的自组装和膜内化特性而作为有效的siRNA载体。设计的肽在10µM范围内均未显示细胞毒性。血清稳定性研究表明，新设计的肽有效地保护siRNA免受核酸酶的早期降解。流式细胞术分析表明，使用新开发的修饰线性肽（MLPs）， siRNA的细胞摄取率为50-90%。Western blot结果显示，在MDA-MB-231和SKOV-3细胞系中靶向STAT3后，蛋白下调幅度超过90%。综上所述，我们开发了一种新的肽类来安全有效地传递siRNA。
RNA interference (RNAi) has drawn enormous attention as a powerful tool because of its capability to interfere with mRNA and protein production. However, designing a safe and efficient delivery system in RNAi therapeutics remains challenging. Herein, we have designed and synthesized several linear peptides containing tryptophan (W) and arginine (R) residues separated by the β-alanine (βA) spacer and attached to a lipophilic fatty acyl chain, cholesterol, or PEG. The peptide backbone sequences were: Ac-C-βA-βA-W4-βA-βA-R4-CO-NH2 and Ac-K-βA-βA-W4-βA-βA-R4-CO-NH2, with only a difference in N-terminal amino acid. The cysteine side chain in the first sequence was used for the conjugation with PEG2000 and PEG550. Alternatively, the side chain of lysine in the second sequence was used for conjugation with cholesterol or oleic acid. We hypothesized that amphiphilic peptides and optimum fatty acyl chain or PEG could function as an effective siRNA carrier by complementing each structural component’s self-assembly and membrane internalization properties. None of the designed peptides showed cytotoxicity up to 10 µM. Serum stability studies suggested that the newly designed peptides efficiently protected siRNA against early degradation by nucleases. Flow cytometry analysis indicated 50–90% cellular uptake of siRNA using the newly developed modified linear peptides (MLPs). Western blot results revealed more than 90% protein downregulation after targeting STAT3 in MDA-MB-231 and SKOV-3 cell lines. In summary, a new peptide class was developed to safely and efficiently deliver siRNA.
登录
查看更多内容
影响因子：
4.6
作者：
Sharma M;El-Sayed NS;Do H;Parang K;Tiwari RK;Aliabadi HM
通讯作者：
Aliabadi HM
影响因子：
4.9
作者：
Mandal, Dindyal;Mohammed, Eman H. M.;Aliabadi, Hamidreza Montazeri
通讯作者：
Aliabadi, Hamidreza Montazeri
影响因子：
4.2
作者：
Welch, Jade J.;Swanekamp, Ria J.;Nilsson, Bradley L.
通讯作者：
Nilsson, Bradley L.
影响因子：
9.5
作者：
Biswas, Abhijit;Chakraborty, Kasturee;Roy, Rituparna Sinha
通讯作者：
Roy, Rituparna Sinha
影响因子：
4.8
作者：
Futaki, S;Suzuki, T;Sugiura, Y
通讯作者：
Sugiura, Y