DNA Conjugates as Tool Compounds for DEL Selections

DEL selections are designed to discover novel small molecule compounds attached to DNA that bind to a target protein. A known small molecule or peptide ligand that binds to the target protein can be conjugated to DNA to mimic compounds contained in DEL libraries. The conjugate can be used as a ligand in preselection binding assays to validate a target protein and optimize selection methods and serve as a positive control in selection experiments. In this chapter, the design, synthesis, and use of DNA conjugate tool compounds are discussed. As an example, I describe the design of a DNA conjugate of a ligand to the CCR5 receptor and its use to optimize selection conditions and as a spike-in positive control in a DEL selection experiment. These methods are broadly applicable to both soluble protein targets and to targets that are displayed on the cell surface and to various types of compounds that can be conjugated to DNA.