Application of Proteins and Genes as Targets to Accelerate Drug Discovery and Development

Traditionally biology has driven the identification and cloning of molecular targets in drug discovery. In recent years, however, an interesting enzyme or receptor, implicated in normal physiology or disease, has been first isolated and characterized, and the gene cloned. Following the expression of the gene using a combination of strategies as described above in a recombinant host, the desirable activity is confirmed. The well-characterized, expressed recombinant protein is then used to implement a high-

throughput compound screen or to support rational drug design. This process could be time-consuming, but it delivers defined targets whose functions are understood. Many of these processes are now automated using advanced robotic technologies that provide precision, efficiency, and reproducibility.

The advent of high-throughput gene sequencing has resulted in the rapid identification of thousands of novel genes, most without known functions. Consequently pharmaceutical scientists are faced with the challenge of transforming genes of unknown function into attractive therapeutic targets, a paradigm shift sometimes called the "from-gene-to-screen" process [35].

The Human Genome Project was initiated on 1 October 1990, and the complete DNA sequence of the human genome will be realized in 2003, two years ahead of schedule. A partial blueprint of the human genome is now available [2]. Gene identification provides a basis for understanding disease at its most fundamental level. The human genome contains approximately 150,000 genes, and individual tissues express between 15,000 and 50,000 of these genes. Gene expression levels often differ in diseased tissue, with certain genes being over- or underexpressed or even entirely eliminated, or new genes being expressed. The localization of differences in gene expression is a crucial step in identifying a potential molecular target for drug discovery. Many believe that knowledge of the genetic control of cellular functions in the postgenomic era will serve as the platform of future strategies for the prevention and treatment of disease.

The identification in the 1980s of the gene thought to be responsible for cystic fibrosis took researchers about nine years to discover, whereas the gene responsible for Parkinson's disease was recently identified within a period of weeks. This extraordinary leap in the ability to associate a

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