遗传密码子扩展技术在蛋白质及多肽类药物中的应用  

Applications of Genetic Code Expansion in Protein and Peptide Drugs

作　　者：高晓威 韦思平 王钦 GAO Xiao-Wei;WEI Si-Ping;WANG Qin(School of Pharmacy,Southwest Medical University,Luzhou 646000,China)

机构地区：[1]西南医科大学药学院,泸州646000

出　　处：《生物化学与生物物理进展》2022年第1期183-201,共19页Progress In Biochemistry and Biophysics

基　　金：中国博士后科学基金(2020M683364);四川省科技计划项目(2020YJ0129,2019JDTD0016)资助。

摘　　要：通过遗传密码子扩展技术位点特异性插入非天然氨基酸(noncanonical amino acids,ncAAs)可在原子水平上对蛋白质的结构与功能进行操控。目前该技术能够向包括高等动植物在内的各种生命体中插入200多种ncAAs,已被广泛应用于生物医药领域。凭借能够在蛋白质中定点引入可控生物正交化学官能团的独特优势,该技术不仅可以用于蛋白质及多肽药物的研发,提高蛋白质及多肽药物的质量与疗效,而且可以为一些人类重大疾病的预防和治疗提供开创性解决方案。本文将重点关注遗传密码子扩展技术的前沿进展及其在各类抗体、细胞因子以及抗菌肽等蛋白质及多肽类药物中的应用,同时也对其衍生的新型生物治疗手段进行简单阐述。Site-specific introduction of noncanonical amino acids(ncAAs)by genetic codon expansion enables manipulation of protein structure and function at the atomic level.More than 200 ncAAs have been incorporated into proteins by this method in different organisms,including plants and animals,and its application has been expanded to the development of new generation biotherapeutics.With the ability to introduce biorthogonal reactive groups into proteins site-specifically,genetic code expansion could not only improve the safety and efficacy of protein and peptide drugs,but also provide a pioneering solution for the prevention and treatment of human diseases.Here,we reviewed recent advances of genetic codon expansion and focused on its applications in protein and peptide drugs.Using genetic codon expansion,homogeneous antibody-drug conjugates with improved pharmacokinetic property could be constructed.Bispecific antibodies with flexible PEG-linkers constructed by ncAAs-based biorthogonal reaction could overcome the spatial arrangement limitation existed in the traditional methods,which generated the bispecific antibodies mainly relying on genetic fusion.Development of genetic codon expansion-based protein switch could improve the efficiency of cell therapy.Site-specifically modified cytokines with PEG and immobilized them on solid surface by genetic codon expansion could also improve their pharmacological properties.Incorporation of immunogenic ncAAs in proteins could elicit immune responses and be used to develop therapeutic protein vaccines.We believe that genetic code expansion could be widely used in the next generation protein and peptide drugs.

关 键 词：遗传密码子扩展技术 非天然氨基酸 抗体 抗菌肽 疫苗 共价交联活性蛋白药物 

分 类 号：Q51[生物学—生物化学]