Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library

Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library

A chemical ligation method for construction of DNA-encoded small-molecule libraries has been developed. Taking advantage of the ability of the Klenow fragment of DNA polymerase to accept templates with triazole linkages in place of phosphodiesters, we have designed a strategy for chemically ligating oligonucleotide tags using cycloaddition chemistry. We have utilized this strategy in the constr...

Discovery of a Covalent Kinase Inhibitor from a DNA-Encoded Small-Molecule Library × Protein Library Selection.

We previously reported interaction determination using unpurified proteins (IDUP), a method to selectively amplify DNA sequences encoding ligand:target pairs from a mixture of DNA-linked small molecules and unpurified protein targets in cell lysates. In this study, we applied IDUP to libraries of DNA-encoded bioactive compounds and DNA-tagged human kinases to identify ligand:protein binding par...

A portable albumin binder from a DNA-encoded chemical library.

Albumin represents the most abundant protein in human plasma, at a concentration of 45 mgmL . To keep physiological production rates to a minimum, albumin displays a long circulatory half-life in mammals thanks to its size above the renal filtration threshold and its unique ability to interact with the neonatal FcRn receptor. Fusions of biopharmaceuticals to albumin or to albumin-binding peptid...

Isolation of high-affinity trypsin inhibitors from a DNA-encoded chemical library.

Discovery of estrogen sulfotransferase inhibitors from a purine library screen.

Center for New Directions in Organic Synthesis, Howard Hughes Medical Institute, and Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, California 94720, Genomics Institute of the Novartis Research Foundation, 3115 Merryfield Row, Suite 200, San Diego, California 92121, Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, N...