Unique quinoline orientations shape the modified aptamer to sclerostin for enhanced binding affinity and bone anabolic potential

Amu Gubu; Yuan Ma; Sifan Yu; Huarui Zhang; Zefeng Chen; Shuaijian Ni; Razack Abdullah; Huan Xiao; Yihao Zhang; Hong Dai; Hang Luo; Yuanyuan Yu; Luyao Wang; Hewen Jiang; Ning Zhang; Yuan Tian; Haitian Li; Aiping Lu; Baoting Zhang; Ge Zhang

doi:10.1016/j.omtn.2024.102146

Unique quinoline orientations shape the modified aptamer to sclerostin for enhanced binding affinity and bone anabolic potential

Mol Ther Nucleic Acids. 2024 Feb 13;35(1):102146. doi: 10.1016/j.omtn.2024.102146. eCollection 2024 Mar 12.

Authors

Amu Gubu^{1

2}, Yuan Ma^{1

2

3}, Sifan Yu^{1

4

5}, Huarui Zhang^{1

4}, Zefeng Chen^{1

2

3}, Shuaijian Ni¹, Razack Abdullah^{1

2

6}, Huan Xiao^{1

4}, Yihao Zhang^{1

4}, Hong Dai¹, Hang Luo^{1

4}, Yuanyuan Yu^{1

2}, Luyao Wang^{1

2}, Hewen Jiang^{1

4}, Ning Zhang^{1

4}, Yuan Tian^{2

6}, Haitian Li^{2

6}, Aiping Lu¹, Baoting Zhang⁴, Ge Zhang^{1

2}

Affiliations

¹ Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery, Hong Kong SAR 999077, China.
² Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China.
³ Increasepharm & Hong Kong Baptist University Joint Centre for Nucleic Acid Drug Discovery, Hong Kong Science Park, New Territories, Hong Kong, China.
⁴ School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
⁵ Shenzhen Research Institute, The Chinese University of Hong Kong, School of Chinese Medicine, The Chinese University of Hong Kong, Shen Zhen 518063, China.
⁶ Institute of Integrated Bioinfomedicine and Translational Science, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tsai, Hong Kong 999077, China.

Abstract

Osteogenesis imperfecta (OI) is a rare genetic disease characterized by bone fragility and bone formation. Sclerostin could negatively regulate bone formation by antagonizing the Wnt signal pathway, whereas it imposes severe cardiac ischemic events in clinic. Our team has screened an aptamer that could promote bone anabolic potential without cardiovascular risk. However, the affinity of the aptamer is lower and needs to be improved. In the study, hydrophobic quinoline molecule with unique orientations (seven subtypes) were incorporated into key sites of a bone anabolic aptamer against sclerostin to form a modified aptamer library. Among all the quinoline modifications, 5-quinoline modification could shape the molecular recognition of modified aptamers to sclerostin to facilitate enhancing its binding to sclerostin toward the highest affinity by interacting with newly participated binding sites in sclerostin. Further, 5-quinoline modification could facilitate the modified aptamer attenuating the suppressed effect of the transfected sclerostin on both Wnt signaling and bone formation marker expression levels in vitro, promoting bone anabolism in OI mice (Col1a2^+/G610C). The proposed quinoline-oriented modification strategy could shape the molecular recognition of modified aptamers to proteins to facilitate enhancing its binding affinity and therapeutic potency.

Keywords: MT: Oligonucleotides: Therapies and Applications; binding affinity; bone anabolic potential; modified aptamer library; quinoline modification; sclerostin aptamer.