DNA-encoded library versus RNA-encoded library selection enables design of an oncogenic noncoding RNA inhibitor

• DOI: 10.1073/pnas.2114971119
• Publication Date: 2022-02-02T20:46:12Z
• Authors: Raphael I. Benhamou; Blessy M. Suresh; Yuquan Tong; Wesley G. Cochrane; Valerie Cavett; Simon Vezina-Dawod; Daniel Abegg; Jessica L. Childs...; Alexander Adibekian; Brian M. Paegel; Matthew D. Disney
• Keywords: 0301 basic medicine; 570; RNA, Untranslated; drug design; Carcinogenesis; 1.1 Normal biological development and functioning; 610; Gene Expression; Triple Negative Breast Neoplasms; Ligands; Cell Line; Small Molecule Libraries; 03 medical and health sciences; Underpinning research; Cell Line, Tumor; Breast Cancer; Drug Discovery; Genetics; Humans; RNA folding; Cancer; Cell Proliferation; Gene Library; Tumor; Untranslated; DNA; Oncogenes; Biological Sciences; 3. Good health; nucleic acids; MicroRNAs; RNA; Biotechnology

Significance Drug discovery generally investigates one target at a time, in sharp contrast to living organisms, which mold ligands and targets by evolution of highly complex molecular interaction networks. We recapitulate this modality of discovery by encoding drug structures in DNA, allowing the entire DNA-encoded library to interact with thousands of RNA fold targets, and then decoding both drug and target by sequencing. This information serves as a filter to identify human RNAs aberrantly produced in cancer that are also binding partners of the discovered ligand, leading to a precision medicine candidate that selectively ablates an oncogenic noncoding RNA, reversing a disease-associated phenotype in cells.