Open AccessDNA-encoded library versus RNA-encoded library selection enables design of an oncogenic noncoding RNA inhibitor
Author(s) -
Raphael I. Benhamou,
Blessy M Suresh,
Yuquan Tong,
Wesley G. Cochrane,
V. Cavett,
Simon VézinaDawod,
Daniel Abegg,
Jessica L. ChildsDisney,
Alexander Adibekian,
Brian M. Paegel,
Matthew D. Disney
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2114971119
Subject(s) - rna , biology , drug discovery , dna , computational biology , microrna , non coding rna , chemical library , gene , phenotypic screening , genetics , ligand (biochemistry) , phenotype , microbiology and biotechnology , small molecule , bioinformatics , receptor
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.