当前位置: X-MOL 学术Theranostics › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
High-Yield Synthesis of Monomeric LMWP(CPP)-siRNA Covalent Conjugate for Effective Cytosolic Delivery of siRNA
Theranostics ( IF 12.4 ) Pub Date : 2017-06-25 , DOI: 10.7150/thno.19863
Junxiao Ye , Ergang Liu , Junbo Gong , Jianxin Wang , Yongzhuo Huang , Huining He , Victor C. Yang

Because of the unparalleled efficiency and universal utility in treating a variety of disease types, siRNA agents have evolved as the future drug-of-choice. Yet, the inability of the polyanionic siRNA macromolecules to cross the cell membrane remains as the bottleneck of possible clinical applications. With the cell penetrating peptides (CPP) being discovered lately, the most effective tactic to achieve the highest intracellular siRNA delivery deems to be by covalently conjugating the drug to a CPP; for instance, the arginine-rich Tat or low molecular weight protamine (LMWP) peptides. However, construction of such a chemical conjugate has been referred by scientists in this field as the “Holy Grail” challenge due to self-assembly of the cationic CPP and anionic siRNA into insoluble aggregates that are deprived of the biological functions of both compounds. Based on the dynamic motion of PEG, we present herein a concise coupling strategy that is capable of permitting a high-yield synthesis of the cell-permeable, cytosol-dissociable LMWP-siRNA covalent conjugates. Cell culture assessment demonstrates that this chemical conjugate yields by far the most effective intracellular siRNA delivery and its corresponded gene-silencing activities. This work may offer a breakthrough advance towards realizing the clinical potential of all siRNA therapeutics and, presumably, most anionic macromolecular drugs such as anti-sense oligonucleotides, gene compounds, DNA vectors and proteins where conjugation with the CPP encounters with problems of aggregation and precipitation. To this end, the impact of this coupling technique is significant, far-reaching and wide-spread.

中文翻译:

高效合成siRNA的单体LMWP(CPP)-siRNA共价共轭物的高产率合成

由于在治疗多种疾病中无与伦比的效率和通用性,siRNA试剂已经发展成为未来的选择药物。但是,聚阴离子siRNA大分子无法穿过细胞膜仍然是可能的临床应用的瓶颈。随着最近发现细胞穿透肽(CPP),实现最高细胞内siRNA递送的最有效策略被认为是将药物共价结合到CPP上。例如,富含精氨酸的Tat或低分子量鱼精蛋白(LMWP)肽。然而,由于阳离子CPP和阴离子siRNA自组装成不溶的聚集体,使这两种化合物的生物学功能丧失,这种化学偶联物的构建被该领域的科学家称为“圣杯”挑战。基于PEG的动态运动,我们在此提出一种简洁的偶联策略,该策略能够实现细胞可渗透的,可溶质解离的LMWP-siRNA共价结合物的高产率合成。细胞培养评估表明,该化学偶联物产生了迄今为止最有效的细胞内siRNA递送及其相应的基因沉默活性。这项工作可能会为实现所有siRNA治疗剂以及大概是大多数阴离子大分子药物(例如反义寡核苷酸)的临床潜力提供突破性进展。与CPP结合的基因化合物,DNA载体和蛋白质会遇到聚集和沉淀的问题。为此,这种耦合技术的影响是巨大的,深远的和广泛的。
更新日期:2017-09-04
down
wechat
bug