肽编码基因转移调节细胞内蛋白质与蛋白质之间的相互作用

IF 4.6 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy-Methods & Clinical Development Pub Date : 2024-02-28 DOI:10.1016/j.omtm.2024.101226
Toshihiko Taya, Daisuke Kami, Fumiya Teruyama, Satoaki Matoba, Satoshi gojo
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引用次数: 0

摘要

肽类药物的发现具有巨大潜力,但当目标是细胞内蛋白质-蛋白质相互作用(PPI)时,细胞膜是一个主要障碍。小分子药物很难靶向 PPI;事实上,目前还没有针对任何细胞内 PPI 的干预工具。在这项研究中,我们开发了一种平台,可以通过基于 mRNA 的基因递送将肽引入细胞。肽长的核酸不能与核糖体稳定结合,几乎不能翻译成蛋白质。在这项研究中,我们创建了一种构建体,将编码二氢叶酸还原酶(DHFR)的序列放在编码目标多肽的序列前面,并加上一个翻译跳转序列,以满足促进核糖体结合和翻译蛋白质快速衰减的要求。这样就能从编码目标蛋白质的 mRNA 开始高效翻译,同时避免不必要的蛋白质残基。通过使用这种构建体,我们发现它可以抑制 Drp1/Fis1 的结合,而 Drp1/Fis1 是细胞内的 PPIs 之一,它控制着线粒体的裂变,这是线粒体动力学的一个重要方面。此外,它还能抑制病理性过度裂变,使线粒体动力学和新陈代谢正常化,并抑制线粒体途径的细胞凋亡。
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Peptide-encoding gene transfer to modulate intracellular protein‒protein interactions
Peptide drug discovery has great potential, but the cell membrane is a major obstacle when the target is an intracellular protein‒protein interaction (PPI). It is difficult to target PPIs with small molecules; indeed, there are no intervention tools that can target any intracellular PPI. In this study, we developed a platform that enables the introduction of peptides into cells via mRNA-based gene delivery. Peptide-length nucleic acids do not enable stable ribosome binding and exhibit little to no translation into protein. In this study, a construct was created in which the sequence encoding dihydrofolate reductase (DHFR) was placed in front of the sequence encoding the target peptide, together with a translation skipping sequence, as a sequence that meets the requirements of promoting ribosome binding and rapid decay of the translated protein. This enabled efficient translation from the mRNA encoding the target protein while preventing unnecessary protein residues. Using this construct, we showed that it can inhibit Drp1/Fis1 binding, one of the intracellular PPIs, which governs mitochondrial fission, an important aspect of mitochondrial dynamics. In addition, it was shown to inhibit pathological hyperfission, normalize mitochondrial dynamics and metabolism, and inhibit apoptosis of the mitochondrial pathway.
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来源期刊
Molecular Therapy-Methods & Clinical Development
Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.90
自引率
4.30%
发文量
163
审稿时长
12 weeks
期刊介绍: The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.
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