The design, pharmacology, and toxicology exploring of a novel chemically modified siRNA targeting hepatic angiotensinogen with potential application for hypertension treatment

Angiotensinogen is the precursor of angiotensin II, a potent vasopressor in the renin-angiotensin-aldosterone system. Small interfering RNAs targeting hepatic angiotensinogen have been proven to be effective on blood pressure lowering in hypertension patients through reducing AGT levels in blood, and such effect could last over 6 months. Existing siRNA molecules has been high effective. However, it may be possible to develop novel siRNA molecules with improved inhibitory activity and longer duration period. In this study, we demonstrated an entire development process for a novel siRNA targeting hepatic angiotensinogen. Through proper combination of bioinformatics on-target/off-target screening on sequences, chemical modification patterns and liver-targeting delivery ligands, we have developed siRNA molecules with equivalent or better inhibitory activity, duration of effect and safety profile compared with siRNA molecules discovered previously. Furthermore, our analysis also revealed the correlation between efficacy and free energy of siRNAs. At present, no model can accurately predict the activity and off-target risk of fully modified siRNA molecules, thus efficient screening procedures are essential during the development of siRNA candidates. This study has provided a detailed and useful reference for the development of potent and safe siRNAs, which could also guide the future development of siRNAs on other targets.血管紧张素原（Angiotensinogen）是血管紧张素II的前体，后者是肾素-血管紧张素-醛固酮系统（renin-angiotensin-aldosterone system）中的强效血管加压剂。靶向肝脏血管紧张素原的小干扰RNA（Small interfering RNAs，siRNA）已被证实可通过降低血液中AGT水平，有效降低高血压患者的血压，且该作用可持续6个月以上。现有siRNA分子已具备较高药效活性，但仍有望开发出抑制活性更强、作用时长更久的新型siRNA分子。本研究完整展示了一款靶向肝脏血管紧张素原的新型siRNA的开发全流程。通过将生物信息学靶点/脱靶点序列筛选、化学修饰模式与肝脏靶向递送配体进行合理组合，我们开发的siRNA分子在抑制活性、作用持续时长与安全性特征方面，均优于或等同于既往开发的siRNA分子。此外，本研究的分析还揭示了siRNA疗效与自由能之间的相关性。目前尚无模型可精准预测完全修饰后的siRNA分子的活性与脱靶风险，因此在siRNA候选分子的开发过程中，高效的筛选流程必不可少。本研究为强效且安全的siRNA开发提供了详尽且实用的参考依据，同时也可为其他靶点的siRNA开发提供指导。