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Unformatted text preview: 35.3 The Analysis of Genomes Holds Great Promise for Drug Discovery The completion of the sequencing of the human and other genomes is a po- tentially powerful driving force for the development of new drugs. Genomic sequencing and analysis projects have vastly increased our knowledge of the proteins encoded by the human genome. This new source of knowledge may greatly accelerate early stages of the drug-development process or even allow drugs to be tailored to the individual patient. Potential Targets Can Be Identified in the Human Proteome The human genome encodes approximately 25,000 proteins, not counting the variation produced by alternative mRNA splicing and posttranslational modifications. Many of these proteins are potential drug targets, in partic- ular those that are enzymes or receptors and have significant biological effects when activated or inhibited. Several large protein families are partic‘ ularly rich sources of targets. For example, the human genome includes genes for more than 500 protein kinases that can be recognized by compar- ing the deduced amino acid sequences. One of them, Bcr—Abl kinase, is known to contribute to leukemias and is the target of the drug imatinib mesylate (Gleevec; p. 401). Some of the other protein kinases undoubtedly play central roles in particular cancers as well. Similarly, the human genome encodes approximately 800 7TM receptors (p. 383) of which approximately 350 are odorant receptors. Many of the remaining 7TM receptors are po- tential drug targets. Some of them are already targets for drugs, such as the B-blocker atenolol, which targets the B-adrenergic receptor, and the antiulcer medication ranitidine (Zantac). The latter compound is an antagonist of the histamine H2 receptor, a 7TM receptor that participates in the control of gastric acid secretion. CH3 0 N/kCH TH 3 Hon H3C \ Atenolol Ranitidine Novel proteins that are not part of large families already supplying drug targets can be more readily identified through the use of genomic informa- tion. There are a number of ways to identify proteins that could serve as tar- gets of drug-development programs. One way is to look for changes in expression patterns, protein localization, or posttranslational modifications in cells from disease-afflicted organisms. Another is to perform studies of tissues or cell types in which particular genes are expressed. Analysis of the human genome should increase the number of actively pursued drug targets by a factor of an estimated two or more. H H N N \ | I No; 1017 M», 35.3 The Promise of Genome Analysis 1018 CHAPTER 35 Drug Development Animal Models Can Be Developed to Test the Validity of Potential Drug Targets The genomes of a number of model organisms have now been sequenced. The most important of these genomes for drug development is that of the mouse. Remarkably, the mouse and human genomes are approximately 85% identical in sequence, and more than 98% of all human genes have rec- ognizable mouse counterparts. Mouse studies provide drug developers with a powerful tool—the ability to disrupt ("knock out”) specific genes in the mouse (p. 1 55). If disruption of a gene has a desirable effect, then the prod- uct of this gene is a promising drug target. The utility of this approach has been demonstrated retrospectively. For example, disruption of the gene for the OL subunit of the H+ -K+ ATPase, the key protein for secreting acid into the stomach, produces mice with less acid in their stomachs. The stomach pH of such mice is 6.9 in circumstances that produce a stomach pH of 3.2 in their wild-type counterparts. This protein is the target of the drugs omeprazole (Prilosec) and lansoprazole (Prevacid and Takepron), used for treating gastric-esophageal reflux disease. ’ O H C O—CH O H C O /©l:N S” 3 3 N S” 3 —\CF />' — />— — . H3C\O N CH5 N \ / Omepruole lansoprazole Several large-scale efforts are underway to generate hundreds or thou- sands of mouse strains, each having a different gene disrupted. The pheno- types of these mice are a good indication of whether the protein encoded by a disrupted gene is a promising drug target. This approach allows drug de- velopers to evaluate potential targets without any preconceived notions re— garding physiological function. Potential Targets Can Be Identified in the Genomes of Pathogens Human proteins are not the only important drug targets. Drugs such as penicillin and HIV protease inhibitors act by targeting proteins within a pathogen. The genomes of hundreds of pathogens have now been se- quenced, and these genome sequences can be mined for potential targets. New antibiotics are needed to combat bacteria that are resistant to many existing antibiotics. One approach seeks proteins essential for cell survival that are conserved in a wide range of bacteria. Drugs that inactivate such proteins are expected to be broad-spectrum antibiotics, useful for treating infections from any of a range of different bacteria. One such protein is peptide deformylase, the enzyme that removes formyl groups that are pres- ent at the amino termini of bacterial proteins immediately after translation (p. 871). Alternatively, a drug may be needed against a specific pathogen. A re- cent example of such a pathogen is the organism responsible for severe acute respiratory syndrome (SARS). Within one month of the recognition of this emerging disease, investigators had isolated the virus that causes the syn- drome, and, within weeks, its 29,751-base genome had been completely se— quenced. This sequence revealed the presence of a gene encoding a viral protease, known to be essential for viral replication from studies of other members of the coronavirus family to which the SARS virus belongs. Drug developers are already at work seeking specific inhibitors of this protease (Figure 35.25). «Q Figure 35.25 Emerging drug target. The structure of a protease from the coronavirus that causes SARS (severe acute respiratory syndrome) is shown bound to an inhibitor. This structure was determined less than a year after the identification of the virus. [Drawn from 1P9S.bdb.] Genetic Differences Influence individual Responses to Drugs Many drugs are not effective in everyone, often because of genetic differ- ences between people. Nonresponding persons may have slight differences in either a drug’s target molecule or proteins taking part in drug transport and metabolism. The goal of the emerging fields of pharmacogenetics and pharmacogenomics is to design drugs that either act more consistently from person to person or are tailored to individuals with particular genotypes. Drugs such as metoprolol that target the Bl-adrenergic receptor are popular treatments for hypertension. H OH N CH H 3 H3C/OXQOHQ Metoprolol But some people do not respond well. Two variants of the gene coding for the (31 -adrenergic receptor are common in the American population. The most common allele has serine in position 49 and arginine in position 389. In some persons, however, glycine replaces one or the other of these residues. In studies, participants with two copies of the most common allele responded well to metoprolol: their daytime diastolic blood pressure was re- duced by 14.7 i 2.9 mm Hg on average. In contrast, participants with one variant allele showed a smaller reduction in blood pressure, and the drug had no significant effect on participants with two variant alleles (Figure 35.26). These observations suggest the potential utility of genotyping indi- viduals at these positions. One could then predict whether or not treatment with metoprolol or other B-blockers is likely to be effective. Given the importance of ADME and toxicity properties in determining drug efficacy, it is not surprising that variations in proteins participating in drug transport and metabolism can alter a drug's effectiveness. An impor- tant example is the use of thiopurine drugs such as 6-thioguanine, 6- mercaptopurine, and azothioprine to treat diseases including leukemia, immune disorders, and inflammatory bowel disease. ‘I 01 9 35.3 The Promise of Genome Analysis 0 —2 .4 —6 -8 —'IO —12 —l4 —16 —18 SR/SR SR/GR SR/SG GR/SG Change In diastolic blood pressure from baseline (mm Hg) Figure 35.26 Phenotype-genotype correlation. Average changes in diastolic blood pressure on treatment with metoprolol. Persons with two copies of the most common (S49R339) allele showed significant decreases in blood pressure. Those with one variant allele (GR or 56) showed more modest decreases, and those with two variant alleles (GR/56) showed no decrease. [From J. A. Johnson et al., Clin. Pharmacol. Ther. 74(2003): 44—52.] ...
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