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*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Article number102073
Number of pages18
JournalMolecular Therapy - Nucleic Acids
Early online date10 Nov 2023
Publication statusPublished - 12 Dec 2023

Scopus Subject Areas

  • Molecular Medicine
  • Drug Discovery

User-Defined Keywords

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


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