治疗性寡核苷酸精确定性表征技术研究进展  

Techniques on Accurate Qualitative Characterization of Therapeutic Oligonucleotides

作　　者：卢嵩 陈娴 王迪 吴枭 王志栋 高运华[1] LU Song;CHEN Xian;WANG Di;WU Xiao;WANG Zhidong;GAO Yunhua(Center for Advanced Measurement Science,National Institute of Metrology,Beijing 100029,China)

机构地区：[1]中国计量科学研究院前沿计量科学中心,北京100029

出　　处：《计量学报》2025年第3期459-466,共8页Acta Metrologica Sinica

基　　金：国家重点研发计划(2023YFF0614603);中国计量科学研究院探索性创新项目(AKYCX2419)。

摘　　要：含有化学基团修饰的治疗性寡核苷酸,是生物药研究的热点领域,应用于疾病治疗领域的优势显著。一方面,寡核苷酸的碱基序列具有特异性,潜在目标靶点广泛,但结合靶点过程存在的脱靶效应及分子构象导致的靶向能力差异也与其碱基序列组成密切相关。另一方面,治疗性寡核苷酸修饰的多重化学结构修饰有助于防止其体内降解,但相应合成路线会伴随结构类似物的杂质产生。对治疗性寡核苷酸的序列和结构进行精确表征,可为治疗性寡核苷酸合成产物以及临床应用提供准确可靠的关键生物分子结构特征信息。因此,对多重修饰寡核苷酸序列的精确测定技术以及合成产物及其结构类似物的分离技术进行深入论述,获取序列长短、序列组成以及杂质构成等结构特征,从而对治疗性寡核苷酸生产过程的质量控制以及临床研究的药物风险评估提供表征技术层面的建议。Therapeutic oligonucleotide with chemical groups modification has been used for the treatment of specific diseases with significant superiorities.The sequence of therapeutic oligonucleotide is designable,for different loci of interest can be targeted by hybridization.However,the sequence of the oligonucleotides can cause risk when being delivered into target regions because of off-target effects or unknown side-effect.And the length of the synthesized products can also be another problem.The modification of therapeutic oligonucleotides is able to prevent its degradation and prolongates the effective drug duration.The solid phase process of the therapeutic oligonucleotides could produce structural analogues of the parent oligonucleotides,thus introducing product impurities.The accurate sequencing and structure characterization of therapeutic oligonucleotides will provide key information for their synthesized product and clinical research.The sequencing techniques and separation techniques of therapeutic oligonucleotides are aim to offer chemical information of the detailed structure,including length,sequence,and impurities,thus the quality control of producing and drug safety assessment can be benefited from the introductions of these techniques.

关 键 词：生物计量 治疗性寡核苷酸 精确表征 质谱测序 杂质分类 色谱分离 

分 类 号：TB99[一般工业技术—计量学]