Molecular Therapy: Nucleic Acids (Mar 2024)

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

Journal volume & issue
Vol. 35, no. 1
p. 102146

Abstract

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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.

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