In addition to considerable research in basic biochemistry and molecular biology that is adding to our understanding of human diseases, the advent of the Human Genome Project (Hudson, 1998) is expected to increase our knowledge base of biological processes enormously and should, in principle, provide the molecular source for all human-based biological targets. The determination of the sequence of all proteins and biological macromolecules from the human genome opens this possibility. However, this research is a classic example of nonhypothesis driven research. That is, one is generating exhaustively the sequence of all human proteins with little or no accompanying knowledge of what these biomolecules do or how they function alone or in concert in the cell or the body. Therefore, realizing the value of this sequence information will require a large investment in basic research. Clearly, it will take decades to reveal the full import of the biological function of all the open reading frames that will be identified as the human genome project progresses to completion over the next 3-4 yr. However, by using bioinformatics judiciously, one can begin to identify most likely candidates for immediate follow-up. Nevertheless, each of these candidate target molecules requires detailed and even intensive study to confirm its general biological role and, in particular, its suitability as a drug discovery candidate for a specific human disease.
Target validation is a very time consuming and labor intensive biological exercise. To speed up this crucial effort, a number of new methodologies, called collectively functional genomics, have been identified. These include array technologies in which a large number of diverse oligonucleotides, representing different gene sequences, are attached to a wafer and used to recognize cDNA/mRNA libraries for particular disease conditions. Other techniques involve knocking out genes to see the effect of their loss. These include antisense and ribozyme methods, as well transgenic animals.
Although the major effort underway is to determine the full human genomic sequence, a significant effort has also begun to sequence the genomes of critical bacteria that are involved in infection. The search for new antibacterial and antiviral targets using genomics is currently an extremely active area of research (Schmid, 1998). It is a remarkable fact that all antibiotics of the past two decades have been aimed at the same very small number of targets, the D-Ala-D-Ala ligases (penicillins and cephalosporins), the ribosome (macrolides), and DNA gyrase (floxacins). Virtually no new targets have emerged. It is anticipated that this situation will change rapidly in the next few years as the results of bacterial genomics are successfully translated into new antibiotic drug discovery targets.
Several examples of the use of genomics to discover new drug targets are beginning to emerge. One such example is the discovery of cathepsin K, a new member of the cysteine protease family that was identified by analyzing new gene sequences from a cDNA library produced from osteoclast cells, cells involved in bone resorption. Subsequent studies indicated that inhibition of this protease may provide a novel therapy for osteoporosis. New chemical entities to inhibit this enzyme are being produced using combinatorial chemistry and structure-based drug design, new technologies that are described later in this chapter (see Section 5.).
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