Molecular genetics is only now beginning tai identify new targets for drug action. For example, regulation of inducible or tissue-specific gene expression has been an obvious but elusive target for pharmacological intervention (233-235). The tools to monitor such events are now available, as in the case of the low density lipoprotein receptor, for which tissue-specific up-regulation of receptor population may successfully compete with other cholesterol-lowering agents (2 36,2 37). In par
allel, another genetic marker for atherosclerotic disease, lipoprotein (a), is a target for selective expression down-regulation (238). An even more direct method to interfere with gene expression is selectively to bind the gene using sequence-specific recognition elements ' that prohibit transcription. Antisense oligo-f nucleotides are the first sequence-directed l molecules designed to inhibit protein expression at the level of translation of mRNA into the undesired protein (239). The first FDA approved drug using antisense technology is Vit-|ravene, introduced by Isis pharmaceuticals in 1998 for local treatment of CMV retinitis in AIDS patients (240a). Genasense, another an-tisense-based drug, designed to block the production of Bcl-2 protein, a protein overex-ipressed in most cancer cells, is in late-stage [clinical trials as an adjunct cancer-treating drug (240b). The ability to test for inhibition easure the effects of ¡ species-specific agents against relevant phar-cological targets in animal models has also been advanced by the development and use of transgenic (240c) or engineered gene knockout animals, such as the CFTR-defective \ mouse for cystic fibrosis (241), in screening | and evaluation procedures.
The power of molecular genetics to provide | unique and valuable tools for drug discovery is
The prospects for |uncovering the molecular etiology of a disease state or for gaining access to a disease-relevant target enzyme or receptor are already being realized. The recent successful mapping of iuman genome (242a, 242b) further promises itter chances of rationally intervening in dis-states at previously inaccessible or un-own points.
The development of recombinant DNA :hnology into a fully integrated component ¡pf* the drug discovery process is inevitable 2c, 243). In 1987, Romberg remarked that ;he two cultures, chemistry and biology, [are] apart even as they discover iore common ground" (244). However, the 'oad area of drug development might qualify one such meeting place for medicinal chem-and molecular biology where the trend is ¡versing. The application of genetic engineer-techniques to biochemical and pharmaco-gical problems will facilitate the discovery of novel therapeutics with potent and selective actions. There is little doubt among medicinal chemists that effective collaboration between chemistry and biology is not only needed but is actually growing in importance in drug design (245,246). The eventual extent of the impact that molecular biology will have on the drug discovery process is, and will be for some time, unknown. However, the reality of recombinant protein therapeutics offers the assurance that this same technology, in conjunction with structural biology, computer-assisted molecular modeling, computational analysis, and medicinal chemistry (247), will help make possible better therapies for those diseases already controllable and new therapies for diseases never before treatable.
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