Chemically modified aptamers for improving binding affinity to the target proteins via enhanced non-covalent bonding

Zefeng Chen; Hang Luo; Amu Gubu; Sifan Yu; Huarui Zhang; Hong Dai; Yihao Zhang; Baoting Zhang; Yuan Ma; Aiping Lu; Ge Zhang

doi:10.3389/fcell.2023.1091809

Chemically modified aptamers for improving binding affinity to the target proteins via enhanced non-covalent bonding

Front Cell Dev Biol. 2023 Feb 23:11:1091809. doi: 10.3389/fcell.2023.1091809. eCollection 2023.

Authors

Zefeng Chen^{1

2}, Hang Luo^{1

2}, Amu Gubu^{1

3}, Sifan Yu⁴, Huarui Zhang⁴, Hong Dai^{1

2}, Yihao Zhang¹, Baoting Zhang⁴, Yuan Ma^{1

2

5}, Aiping Lu^{1

2

5}, Ge Zhang^{1

2

5}

Affiliations

¹ Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China.
² Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon, Hong Kong SAR, China.
³ Aptacure Therapeutics Limited, Kowloon, Hong Kong SAR, China.
⁴ School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.
⁵ Institute of Precision Medicine and Innovative Drug Discovery, HKBU Institute for Research and Continuing Education, Shenzhen, Hong Kong SAR, China.

Abstract

Nucleic acid aptamers are ssDNA or ssRNA fragments that specifically recognize targets. However, the pharmacodynamic properties of natural aptamers consisting of 4 naturally occurring nucleosides (A, G, C, T/U) are generally restricted for inferior binding affinity than the cognate antibodies. The development of high-affinity modification strategies has attracted extensive attention in aptamer applications. Chemically modified aptamers with stable three-dimensional shapes can tightly interact with the target proteins via enhanced non-covalent bonding, possibly resulting in hundreds of affinity enhancements. This review overviewed high-affinity modification strategies used in aptamers, including nucleobase modifications, fluorine modifications (2'-fluoro nucleic acid, 2'-fluoro arabino nucleic acid, 2',2'-difluoro nucleic acid), structural alteration modifications (locked nucleic acid, unlocked nucleic acid), phosphate modifications (phosphorothioates, phosphorodithioates), and extended alphabets. The review emphasized how these high-affinity modifications function in effect as the interactions with target proteins, thereby refining the pharmacodynamic properties of aptamers.

Keywords: aptamer; chemical modification; high affinity; interaction; non-covalent bonding.

Publication types

Review

Grants and funding

This study was supported by the Guangdong Basic and Applied Basic Research Foundation (2020A1515110630), the Hong Kong General Research Fund (HKBU 12114416, HKBU 12101117, HKBU 12100918, HKBU 12101018, HKBU 12103519, and HKBU 14100218), the National Key R&D Program of China (2018YFA0800804).