Techniques Of Discovery

The newer technologies, the impact of which have yet to be fully felt include:

6 The cost of development of a new chemical entity (NCE) (a novel molecule not previously tested in humans) from synthesis to market (general clinical use) is estimated at US$ 500 million; the process may take as much as 15 years (including up to 10 years of clinical studies), which is relevant to duration of patent life and so to ultimate profitability; if the developer does not see profit at the end of the process, the investment will not be made. The drug may fail at any stage, including the ultimate, i.e. at the official regulatory body after all the development costs have been incurred. It may also fail (due to adverse effects) within the first year after marketing, which constitutes a catastrophe (in reputation and finance) for the developer as well as for some of the patients.

Pirated copies of full regulatory dossiers have substantial black market value to competitor companies who have used them to leap-frog the original developer to obtain a licence for their unresearched copied molecule. Dossiers may be enormous, even one million pages or the electronic equivalent, the latter being very convenient as it allows instant searching.

Molecular modelling aided by three-dimensional computer graphics (including virtual reality) allows the design of structures based on new and known molecules to enhance their desired, and to eliminate their undesired, properties to create highly selective targeted compounds. In principle all molecular structures capable of binding to a single high-affinity site can be modelled.

Combinatorial chemistry involves the random mixing and matching of large numbers of chemical building blocks (amino acids, nucleotides, simple chemicals) to produce 'libraries' of all possible combinations. This technology can generate billions of new compounds that are initially evaluated using automated robotic high-throughput screening devices that can handle thousands of compounds a day.7 These screens utilise radio-labelled ligand displacement on single human receptor subtypes or enzymes on nucleated (eukaryotic) cells. If the screen records a positive response the compound is further investigated using traditional laboratory methods, and the molecule is manipulated to enhance selectivity and/or potency (above).

Proteins as medicines: biotechnology. The targets of most drugs are proteins (cell receptors, enzymes) and it is only lack of technology that has hitherto prevented the exploitation of proteins (and peptides) as medicines. This technology is now available. But there are great practical problems in getting the proteins to the target site in the body (they are digested when swallowed and cross cell membranes with difficulty).

Biotechnology involves the use of recombinant DNA technology/genetic engineering to clone and

7 'It is too early to say what success these programmes may have but automation of assays, possibly coupled to similar automation of syntheses, promises to speed up the search for new leads which is the rate-limiting step in the introduction of really novel therapeutic agents. Their value in medicine will depend upon the significance of the control mechanism concerned in the pathogenesis of a disease process. Critics fear that the result may well be large numbers of drugs in search of a disease to treat' (CT Dollery, ibidem). The demand for competent clinical trialists, already great, will increase to meet the demand; the financial rewards to competent (and honest) clinical trialists are great, in the competitive world of drug introduction (see also McNamee D 1995 Lancet 345:1167).

express human genes, for example, in microbial, Escherichia coli or yeast, cells so that they manufacture proteins that medicinal chemists have not been able to synthesise; they also produce hormones and autacoids in commercial amounts (such as insulin and growth hormone, erythropoietins, cell growth factors and plasminogen activators, interferons, vaccines and immune antibodies). Transgenic animals (that breed true for the gene) are also being developed as models for human disease as well as for production of medicines.

The polymerase chain reaction (PCR) is an alternative to bacterial cloning. This is a method of gene amplification that does not require living cells; it takes place in vitro and can produce (in a cost-effective way) commercial quantities of pure potential medicines.

Genetic medicines. Synthetic oligonucleotides are being developed to target sites on DNA sequences or genes (double strand DNA: triplex approach) or messenger RNA (the antisense approach) so that the production of disease-related proteins is blocked. These oligonucleotides offer prospects of treatment for cancers and viruses without harming healthy tissues.8

Gene therapy of human genetic disorders is 'a strategy in which nucleic acid, usually in the form of DNA, is administered to modify the genetic repertoire for therapeutic purposes', e.g. cystic fibrosis. 'The era of "the gene as drug" is clearly upon us' (R G Crystal). Significant problems remain; in particular the methods of delivery. Three methods are available: an injection of 'naked' DNA; using a virus as carrier with DNA incorporated into its genome; or DNA encapsulated within a liposome.

Immunopharmacology. Understanding of the molecular basis of immune responses has allowed the definition of mechanisms by which cellular function is altered by a legion of local hormones or autacoids in, for example, infections, cancer, autoimmune diseases, organ transplant rejection. These processes present targets for therapeutic intervention. Hence the rise of immunopharmacology

8 Cohen J S, Hogan M E 1994 The new genetic medicines.

Scientific American (Dec): 50-55.

Positron emission tomography (PET) allows noninvasive pharmacokinetic and pharmacodynamic measurements in previously inaccessible sites, e.g. the brain in intact humans and animals.

Older approaches to discovery of new medicines that continue in use include:

• Animal models of human disease or an aspect of it of varying relevance to man.

• Natural products, the basis for many of today's medicines for pain, inflammation, cancer, cardiovascular problems. Modern technology for screening has revived interest and intensified the search by multinational pharmaceutical companies which scour the world for leads from microorganisms (in soil or sewage or even from insects entombed in amber 40 million years ago), from fungi, plants and animals. Developing countries in the tropics (with their luxuriant natural resources) are prominent targets in this search and have justly complained of exploitation ('gene robbery'). Many now require formal profit-sharing agreements to allow such searches

• Traditional medicine, which is being studied for possible leads to usefully active compounds

• Modifications of the structures of known drugs; these are obviously likely to produce more agents having similar basic properties, but may deliver worthwhile improvements. It is in this area that the much-complained-of, me-too and me-again drugs are developed (sometimes purely for commercial reasons).

• Random screening of synthesised and natural products.

• New uses for drugs already in general use as a result of intelligent observation and serendipity,9 or advancing knowledge of molecular mechanisms, e.g. aspirin for antithrombosis effect.

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