A bimolecular modification strategy for developing long-lasting bone anabolic aptamer

Huarui Zhang; Sifan Yu; Shuaijian Ni; Amu Gubu; Yuan Ma; Yihao Zhang; Haitian Li; Yuzhe Wang; Luyao Wang; Zongkang Zhang; Yuanyuan Yu; Aiping Lyu; Baoting Zhang; Ge Zhang

doi:10.1016/j.omtn.2023.102073

A bimolecular modification strategy for developing long-lasting bone anabolic aptamer

Mol Ther Nucleic Acids. 2023 Nov 10:34:102073. doi: 10.1016/j.omtn.2023.102073. eCollection 2023 Dec 12.

Authors

Huarui Zhang¹, Sifan Yu^{1

2

3}, Shuaijian Ni², Amu Gubu⁴, Yuan Ma⁴, Yihao Zhang¹, Haitian Li⁴, Yuzhe Wang⁵, Luyao Wang⁴, Zongkang Zhang¹, Yuanyuan Yu⁴, Aiping Lyu⁴, Baoting Zhang¹, Ge Zhang⁴

Affiliations

¹ School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
² Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
³ Guangdong-Hong Kong-Macao Greater Bay Area International Research Platform for Aptamer-based Translational Medicine and Drug Discovery, Hong Kong SAR, China.
⁴ Law Sau Fai Institute for Advancing Translational Medicine in Bone and Joint Diseases, Hong Kong Baptist University, Hong Kong SAR, China.
⁵ The Second Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou, China.

Abstract

The molecular weight of nucleic acid aptamers (20 kDa) is lower than the cutoff threshold of the renal filtration (30-50 kDa), resulting in a very short half-life, which dramatically limits their druggability. To address this, we utilized 3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(4-hydroxy-2-oxo-2H-chromen-6-yl)propenamide (HC) and 12-((2,5-dioxopyrrolidin-1-yl)oxy)-12-oxododecanoic acid (DA), two newly designed coupling agents, for synergistic binding to human serum albumin (HSA). Both HC and DA are conjugated to a bone anabolic aptamer (Apc001) against sclerostin to form an Apc001OC conjugate with high binding affinity to HSA. Notably, HC and DA could synergistically facilitate prolonging the half-life of the conjugated Apc001 and promoting its bone anabolic potential. Using the designed blocking peptides, the mechanism studies indicate that the synergistic effect of HC-DA on pharmacokinetics and bone anabolic potential of the conjugated Apc001 is achieved via their synergistic binding to HSA. Moreover, biweekly Apc001OC at 50 mg/kg shows comparable bone anabolic potential to the marketed sclerostin antibody given weekly at 25 mg/kg. This proposed bimolecular modification strategy could help address the druggability challenge for aptamers with a short half-life.

Keywords: MT: Oligonucleotides: Therapies and Applications; aptamers; long-lasting modification; low-molecular-weight coupling agents; osteogenesis imperfecta; sclerostin.