Gene expression as a target for new drug discovery

Abstract

Over the last 7 years we have carried out a major research effort focused on gene transcription as a novel approach to drug discovery. The goal is to identify small molecular weight compounds that modulate the expression of a target gene in a specific manner, thereby either increasing or decreasing the concentration of the corresponding protein product. Transcriptional modulation not only provides a potential means to replace recombinant proteins as drugs, but also provides a novel approach to manipulate key gene targets in many therapeutic areas. This article describes some of the features and advantages of transcription-based pharmaceuticals and illustrates how this approach can be applied to drug discovery with a program we are pursuing to identify new treatments for sickle cell disease and beta-thalassemia.

FIG. 1

Schematic representation of the 100-kb human β-globin locus.

FIG. 2

Schematic representation of the δ- and β-globin promoter/luciferase fusion plasmids.

FIG. 3

Frequency distribution of 16,000 fungal extracts screened. As expected, the majority of the extracts do not have any effect on δ-globin luciferase transcription. TIR = transcription induction ratio, or the signal of the sample signal of DMSO control.