Selection and characterization of DNA aptamers inhibiting a druggable target of osteoarthritis, ADAMTS-5

Yuanyuan Yu, Mengping Liu, Vanessa N.T. Choi, Yee Wai Cheung, Julian A. Tanner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

There is a critical need for the development of more potent inhibitors for osteoarthritis (OA) therapy given the poor life quality of arthritis patients. Aggrecanase ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) is an established drug target identified for osteoarthritis. In this study, we evolved and characterized two new DNA aptamer inhibitors of ADAMTS-5, namely apt21 and apt25. The aptamers exhibited nanomolar binding affinity and high specificity against ADAMTS-5. KD values of apt21 and apt25 were determined by the Enzyme-linked Oligonucleotide Assay (ELONA) at 1.54 ± 0.16 nM and 1.79 ± 0.08 nM, respectively. Circular Dichroism (CD) analysis demonstrated that both aptamers formed monovalent cation dependent G-quadruplex structures. Calcium ions did not affect the binding of the aptamers to ADAMTS-5. The inhibitory effects of apt21 and apt25 on ADAMTS-5 were evaluated by the Förster Resonance Energy Transfer (FRET) assay, in which IC50 values of apt21 and apt25 were estimated at 52.76 ± 6.70 μM and 61.14 ± 9.67 μM, respectively. These two aptamers are the first DNA G-quadruplex aptamers demonstrated to inhibit ADAMTS-5 and could have value for OA therapy.

Original languageEnglish
Number of pages9
JournalBiochimie
DOIs
Publication statusE-pub ahead of print - 11 Jun 2022

Scopus Subject Areas

  • Biochemistry

User-Defined Keywords

  • ADAMTS-5
  • DNA aptamers
  • G-quadruplex
  • Inhibitor
  • Osteoarthritis

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