FRET-Based Probe for High-Throughput DNA Intercalator Drug Discovery and in Vivo Imaging

Chandrashekhar U. Murade, Samata Chaudhuri, Ibtissem Nabti, Hala Fahs, Fatima S.M. Refai, Xin Xie, Yanthe E. Pearson, Kristin C. Gunsalus, George T. Shubeita

Research output: Contribution to journalArticlepeer-review


Molecules that bind DNA by intercalating its bases remain among the most potent cancer therapies and antimicrobials due to their interference with DNA-processing proteins. To accelerate the discovery of novel intercalating drugs, we designed a fluorescence resonance energy transfer (FRET)-based probe that reports on DNA intercalation, allowing rapid and sensitive screening of chemical libraries in a high-throughput format. We demonstrate that the method correctly identifies known DNA intercalators in approved drug libraries and discover previously unreported intercalating compounds. When introduced in cells, the oligonucleotide-based probe rapidly distributes in the nucleus, allowing direct imaging of the dynamics of drug entry and its interaction with DNA in its native environment. This enabled us to directly correlate the potency of intercalators in killing cultured cancer cells with the ability of the drug to penetrate the cell membrane. The combined capability of the single probe to identify intercalators in vitro and follow their function in vivo can play a valuable role in accelerating the discovery of novel DNA-intercalating drugs or repurposing approved ones.

Original languageEnglish (US)
Pages (from-to)2233-2240
Number of pages8
JournalACS Sensors
Issue number6
StatePublished - Jun 25 2021


  • DNA intercalators
  • antimicrobials
  • cancer therapy
  • drug discovery
  • drug screen
  • oligo
  • probe
  • sensor

ASJC Scopus subject areas

  • Bioengineering
  • Instrumentation
  • Process Chemistry and Technology
  • Fluid Flow and Transfer Processes


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