Drug discovery and development
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Human disease The wide range of diseases to which humans are exposed have in common the fact that each is the result of either some physiological dysfunction caused by a gene mutation or incorrect expression of the related protein, or of the exposure of the individual to an environmental factor, such as pesticides, diet, or bacterial, fungal or viral infection. The dysfunction gives rise to characteristic medical symptoms that enable the condition to be diagnosed, commonly by diagnostic tests of the type described in Chapter 16, and an evaluation made of the severity of the condition and the future prospects of the patient making a full recovery from it. Underlying many of the conditions at a molecular level is a change in the amount, function or activity of one or more proteins that in turn trigger changes in cellular, tissue or organ function. A large part of current worldwide medical research is aimed at the elucidation of the molecular mechanisms underlying diseases such as the various forms of cancer and neurological conditions such as Parkinson’s disease, motor neurone disease and multiple sclerosis, in order to identify key proteins involved in the disease process with a view to selecting one of the proteins as a target for the development of a new drug and thereby to minimise or eliminate the symptoms. 18.1.2 The nature of drugs and their target proteins At the present time there are just over 800 drugs in current use worldwide. The majority are organic molecules with a molecular weight of less than 500. However, other possibilities for the nature of the drug are receiving increasing attention. One such option is to develop a monoclonal antibody as the drug to target the protein. Thus an increasing number of monoclonal antibodies are being developed for the 709 treatment of specific forms of cancer. An example is transtuzumab (Herceptin®) used in the treatment of breast cancer. An alternative approach is to develop drugs to modify the expression of the gene producing the target protein rather than the protein itself. Our knowledge of gene replication and transcription has advanced to the stage where it has become possible to target the DNA or RNA responsible for the biosynthesis of a specific protein. Strategies based on the interference with the translation of mRNA, a process referred to as RNA interference (RNAi) have shown considerable potential in model studies (Section 6.8.5). Short interfering RNAs (siRNAs), for example, can be synthesised with a specific base sequence designed to complement and inactivate specific mRNAs or whole gene families. They work by activating a sequence-specific RNA-induced silencing complex (RISC) that cleaves the corresponding functional mRNA within the cell. Some siRNA ‘libraries’ are now available commercially. The main challenge with RNAi therapy is to devise an effective delivery system for the siRNAs as conventional oral administration would inevitably lead to their premature metabolism. A related potential therapy is the use of so-called DNAzymes. These are synthetic, single-stranded deoxyribonucleotides with the ability to bind and cleave RNA and thereby to suppress the expression of pathophysiologically active genes, for example in a number of cardiovascular states. They have the advantage over antisense molecules that they are less sensitive to nuclease activity. Advances in recombinant DNA technology, particularly the discovery of restriction endonucleases, polynucleotide ligase and DNA polymerase (Section 5.5), created the technique of gene replacement therapy to correct inherited or acquired genetic defects affecting the availability of a specific protein underlying a disease state.
DNA can be introduced into targeted cells, most commonly by incorporating it into a vector such as a modified virus, so there is strong reason to believe that this will become an increasingly important form of therapy in the future (see Table 6.9). Equally, cell-based therapies, particularly those based on the use of stem cells (Section 2.6), have proved to be successful in animal models and there is every reason to expect their future adaptation to the treatment of human disease. The following discussion will concentrate on the discovery and development of small organic molecules as drugs but many of the principles and challenges discussed are equally applicable to these alternative forms of therapy. The vast majority of these small organic drugs target one of three specific types of proteins namely enzymes, membrane or nuclear receptors and transporters. It has been estimated that the current total number of different protein targets used by marketed drugs in humans is approximately 500. Nearly three-quarters of these targets are human proteins, the remainder are proteins in infecting organisms. Of those aimed at human targets nearly one-third are aimed at G-protein-coupled receptors (GPCRs) (Section 17.4.3) and one-third at enzymes. 18.1.3 Case studies To illustrate how drug development is based on the targeting of a specific protein, three common human disorders – hypertension (high blood pressure), dyspepsia (heartburn) and bacterial infection – will be considered briefly. Two others, cardiovascular disease and HIV/AIDS are considered in greater detail in Section 18.2.2. 710 Drug discovery and development It is evident from these case studies that a specific therapeutic outcome can be achieved by targeting one of a number of possible proteins. The challenge in the process of discovering and developing a new drug is firstly to identify the possible targets and then to take an informed decision on which one to select for the discovery process. Case study 1 HYPERTENSION Hypertension, also referred to as high blood pressure (bp), is defined as a systolic bp >140 mm Hg and a diastolic bp >90 mm Hg. Its cause may be primary or secondary to a range of conditions such as kidney disease. If unchecked, hypertension can lead to strokes and heart attacks. It can be reduced by a number of drugs acting by significantly different mechanisms: • b1adrenergic receptor antagonists such as propranolol and labetalol and the a1adrenergic receptor antagonist prazosin involve the blocking of the action of GPCRs. • Inhibitors, such as captopril, of angiotensin converting enzyme (ACE), which converts angiotensin I to angiotensin II that in turn leads to an increase in blood pressure by its action on angiotensin II receptor, are the preferred first choice therapy to lower bp. • Antagonists of the GPCR angiotensin II receptor, such as telmisartan, are a related drug therapy to that of ACE inhibitors. • Antagonists of the dihydropyridine Ca2þ channel, such as nifedipine and verapamil, that block the movement of Ca2þ ions into smooth muscle cells lining coronary arteries and thereby lower bp, are also valuable therapeutic agents for the treatment of hypertension. • Inhibitors of phosphodiesterases (PDE) found in vascular smooth muscle and involved in contractility, also reduce blood pressure. One such inhibitor is silendafil (Viagra®) but it specifically inhibits PDE5 which hydrolyses cGMP to 50 -GMP and thereby enhances the action of nitric oxide induced penile erection and is therefore widely prescribed for erection dysfunction and not for the treatment of hypertension! Case study 2 DYSPEPSIA (INDIGESTION) Dyspepsia presents as upper abdominal pain and is associated with excess production of acid in the stomach. If simple antacids are inadequate for its alleviation, drugs are available to reduce the acid secretion. In the 1970s it was shown that antagonists of the GPCR histamine H2-receptor successfully inhibit stomach acid production. The first clinically used antagonist was cimetidine but it was soon replaced by ranitidine due to its better tolerability, longer action and greater activity.
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