Identification of TrkB Binders from Complex Matrices Using a Magnetic Drug Screening Nanoplatform

Zekiye Ceren Arituluk, Jesse Horne, Bishnu Adhikari, Jeffrey Steltzner, Shomit Mansur, Parmanand Ahirwar, Sadanandan E. Velu, Nora E. Gray, Lukasz M. Ciesla, Yuping Bao

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) have been shown to play an important role in numerous neurological disorders, such as Alzheimer's disease. The identification of biologically active compounds interacting with TrkB serves as a drug discovery strategy to identify drug leads for neurological disorders. Here, we report effective immobilization of functional TrkB on magnetic iron oxide nanoclusters, where TrkB receptors behave as "smart baits"to bind compounds from mixtures and magnetic nanoclusters enable rapid isolation through magnetic separation. The presence of the immobilized TrkB was confirmed by specific antibody labeling. Subsequently, the activity of the TrkB on iron oxide nanoclusters was evaluated with ATP/ADP conversion experiments using a known TrkB agonist. The immobilized TrkB receptors can effectively identify binders from mixtures containing known binders, synthetic small molecule mixtures, and Gotu Kola (Centella asiatica) plant extracts. The identified compounds were analyzed by an ultrahigh-performance liquid chromatography system coupled with a quadrupole time-of-flight mass spectrometer. Importantly, some of the identified TrkB binders from Gotu Kola plant extracts matched with compounds previously linked to neuroprotective effects observed for a Gotu Kola extract approved for use in a clinical trial. Our studies suggest that the possible therapeutic effects of the Gotu Kola plant extract in dementia treatment, at least partially, might be associated with compounds interacting with TrkB. The unique feature of this approach is its ability to fast screen potential drug leads using less explored transmembrane targets. This platform works as a drug-screening funnel at early stages of the drug discovery pipeline. Therefore, our approach will not only greatly benefit drug discovery processes using transmembrane proteins as targets but also allow for evaluation and validation of cellular pathways targeted by drug leads.

Original languageEnglish (US)
Pages (from-to)6244-6255
Number of pages12
JournalACS Applied Bio Materials
Volume4
Issue number8
DOIs
StatePublished - Aug 16 2021

Keywords

  • BDNF/TrkB
  • drug discovery
  • magnetic nanoclusters
  • neurologic disorders
  • plant extract
  • receptor immobilization

ASJC Scopus subject areas

  • Chemistry(all)
  • Biomaterials
  • Biomedical Engineering
  • Biochemistry, medical

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